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Seminars in Oncology Nursing, Vol 30, No 2 (May), 2014: pp 84-99

PRECISION MEDICINE FOR NURSES: 101 COLLEEN LEMOINE OBJECTIVES: To introduce the key concepts and terms associated with precision medicine and support understanding of future developments in the field by providing an overview and history of precision medicine, related ethical considerations, and nursing implications. DATA SOURCES: Current nursing, medical and basic science literature. CONCLUSION: Rapid progress in understanding the oncogenic drivers associated with cancer is leading to a shift toward precision medicine, where treatment is based on targeting specific genetic and epigenetic alterations associated with a particular cancer.

IMPLICATIONS

FOR NURSING PRACTICE: Nurses will need to embrace the paradigm shift to precision medicine, expend the effort necessary to learn the essential terminology, concepts and principles, and work collaboratively with physician colleagues to best position our patients to maximize the potential that precision medicine can offer.

KEY WORDS: Precision medicine, biomarkers, mutation testing, therapeutic targets

I

T is 2002, and Mary is an oncology nurse who works in a chemotherapy infusion center. In addition to daily chemotherapy administration, Mary facilitates a monthly lung cancer education and support group. Attending this month’s meeting are four patients who have been recently diagnosed with metastatic non–small cell lung cancer (NSCLC). They have Colleen Lemoine, APRN, MN, AOCNÒ, RN-BC: Oncology Clinical Specialist, Amgen. Address correspondence to Colleen Lemoine, APRN, MN, AOCNÒ, RN-BC, Oncology Clinical Specialist, Amgen, 5520 York St., New Orleans, LA 70125. e-mail: [email protected] Ó 2014 Elsevier Inc. All rights reserved. 0749-2081/3002-$36.00/0. http://dx.doi.org/10.1016/j.soncn.2014.03.002

each begun therapy within the past 2 weeks and are discussing their experiences with their therapies. Each is being treated with platinum doublet chemotherapy, either cisplatin or carboplatin combined with paclitaxel. As part of Mary’s chemotherapy administration responsibilities, she routinely verifies orders against current drug and regimen references, and she knows that platinum doublet therapy is appropriate for patients with advanced or metastatic NSCLC. Because all four patients are receiving similar regimens, the information and education Mary provides is helpful to everyone in the group, and they agree that it is reassuring to them that they are all getting the same treatment for the same disease. It is now 2013, and Mary is still working in the chemotherapy infusion center and facilitating the monthly lung cancer education and support

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group. Attending this month’s meeting are six patients, all of whom have been recently diagnosed with metastatic NSCLC and all of whom have started therapy within the past 2 weeks. Despite all of the patients being diagnosed with the same stage of NSCLC, these six patients are receiving different therapies. This seeming inconsistency is very distressing to the patients who wonder out loud why they all cannot be on oral therapies like some of them are and why those getting intravenous therapies are all getting different drugs. Mary explains that in the past, the differences in NSCLCs were not fully understood or appreciated and so patients with NSCLC were treated similarly. Mary continues to explain that in the past decade, however, significant progress has been made in understanding the differences in various NSCLCs and in developing specific therapies for the different types. Historically, therapy was based on whether the patient had small cell lung cancer or NSCLC and the stage of the cancer. Now, within NSCLC, therapies are based on squamous versus nonsquamous histology, and the presence or absence of specific genetic mutations* associated with NSCLCs, including epidermal growth factor receptor (EGFR) mutations, or anaplastic lymphoma kinase (ALK) rearrangements. Additionally, other genetic mutations such as those in the Kirsten rat sarcoma (KRAS) gene, while not presently associated with a specific therapy, serve as prognostic and predictive biomarkers. Mary reassures the patients that the diversity in therapies is reflective of the genetic diversity underlying their diseases. The patients all agree that they are reassured knowing that they are getting the treatment that best matches the genetic characteristics of their tumors. As with NSCLC, significant strides have been made in understanding the genetic mutations associated with other tumor types as well. Mary observes that for most cancers, an emerging paradigm shift in treatment – toward precision medicine - is under way, with the goal of providing each patient with the therapy most likely to benefit them based on genetic characteristics of the tumor and of the patient themselves.

*

Readers can find the definitions of the underlined words in Appendix A. Glossary at the end of this manuscript.

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Oncology nurses have a professional responsibility to remain up-to-date with current knowledge about cancer and its treatment. In order for nurses to continue to provide quality care for patients with cancer, it is essential that they understand precision medicine and its implications for therapy and patient education. The purpose of this article is to provide an introduction to the key concepts and terms associated with precision medicine and to provide a foundation to support understanding of future developments in the field. What follows is an overview of precision medicine, the scientific advances that have made it possible, related ethical considerations and the nursing implications of caring for patients with cancer in an era of precision medicine.

EVOLUTION OF PRECISION MEDICINE IN ONCOLOGY A forerunner to precision medicine was personalized medicine. Personalized medicine as defined in the Priorities for Personalized Medicine (President’s Council of Advisors on Science and Technology [PCAST], 2008), ‘‘refers to the tailoring of medical treatment to the individual characteristics of each patient’’.1(p. 1) Rather than aiming to create patient-specific drugs for each individual patient, the goal of personalized care, as described in the 2008 PCAST report, is to allow for the clustering of patients into subpopulations according to their risk for a given health condition or their response to a particular therapy. This definition differs from the more general historical definition of the term personalized, which has been used to characterize the individualized approach to patient care. The scope and practice of nursing highlights the importance of an individualized plan of care based on accurate and ongoing assessment, diagnosis, outcome identification, intervention and evaluation. While some approaches, such as vaccinations, use a single strategy for virtually all patients, most therapeutic plans rely on individualized interventions to achieve the desired outcomes. Consider an infectious process exemplar. Selecting the appropriate therapy is dependent not only on identifying the causative organism but also on considering the individual patient’s ability to tolerate therapy based on allergy status, organ function, and side-effect profile. Additionally, with some anti-infective therapies, dose adjustments are necessary based on individual

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variations, such as renal function. While selecting therapies based on individual characteristics is a well-established approach to patient care, the 2008 PCAST report notes: ‘‘(However) recent rapid advances in genomics and molecular biology are beginning to reveal a large number of possible new, genome-related molecular markers for the presence of disease, susceptibility to disease, or differential response to treatment. Such markers can serve as the basis of new genomics-based diagnostic tests for identifying and/or confirming disease, assessing an individual’s risk of disease, identifying patients who will benefit from particular interventions, or tailoring dosing regimens to individual variations in metabolic response. The new diagnostics can also pave the way for development of new therapeutics specifically targeted at the physiological consequences of the genetic defect(s) associated with the patient’s disease.’’1(p. 1) In 2011, the National Academies published the recommendations of a multidisciplinary committee convened specifically to consider the need for a new framework to categorize human disease given the recent advances in molecular biology.2 Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease resulted from the committee’s work and within it, the suggested term Precision Medicine, which aimed to capture the concept of personalized medicine while clarifying that it does not mean that each person receives a unique therapy, different from every other patient’s treatment. Building on the PCAST work, the National Academies committee characterized precision medicine as: ‘‘the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology and/or prognosis of those diseases they may develop, or in their response to a specific treatment. Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not.’’2(p. 125) The National Academies committee notes that the use of the term precision in ‘‘precision medicine’’ is meant to convey both accuracy and precision.

The evolving concepts within personalized and precision medicine can be more clearly appreciated when viewing the progress in therapies available for patients with cancer. Initial cancer therapies were selected based primarily on cancer type and stage. Traditional cytotoxic chemotherapy was specific in its mechanism of action – targeting cells that were actively dividing – but non-selective, in that it affected both malignant and healthy cell populations that were rapidly proliferating. Research into cancer pathology improved our understanding of the variations in cancers, even those arising from the same anatomical site. Hormone receptor status in breast cancer was identified as a predictive biomarker and cancer therapeutics became increasingly selective. Moving toward a more precise approach, breast cancers began to be routinely evaluated for hormone-receptor status and treatment regimens began to incorporate anti-estrogen therapy for those patients with hormone-receptor–positive disease. Anti-estrogen therapy was not given to patients with hormone-receptor–negative disease as there is no appreciable benefit to be realized in this population. Continued research led to the identification of additional predictive biomarkers in breast cancers and non-Hodgkin lymphomas. CD20-positive lymphomas began to be treated with rituximab therapy and breast cancers associated with the overexpression of HER2 were identified as appropriate for trastuzumab therapy. In addition to being predictive biomarkers, hormone receptor status and HER2 overexpression were considered prognostic biomarkers as well. A breast cancer that was neither hormone receptor-positive nor HER2-overexpressing came to be known as triple negative breast cancer and women with this type of disease had poorer prognoses than their counterparts with hormone-receptor–positive, HER2-overexpressing disease. Efforts to identify pathological and cellular differences associated with various tumors continued and as new differences were identified, efforts followed to develop therapeutics that capitalized on those differences. The term targeted therapy emerged as an umbrella term to categorize both the monoclonal antibodies (MABs) and the small molecule agents that targeted these molecular and cellular differences. The use of the term targeted therapy to selectively describe MABs and small-molecule agents is somewhat misleading because it implies that other agents

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are not targeted, or that they lack a target. In fact, all drugs have a target, usually described in the mechanism-of-action section of the Food and Drug Administration (FDA)-approved prescribing information, although there are drugs for which the mechanism of action is not known or fully understood. The term precision medicine more accurately describes the evolution of cancer therapeutics towards mechanisms that increasingly capitalize on the specific cellular abnormalities associated with cancer.

GENETICS Normal Genetics At the most fundamental level, cancer is a genetic disease. Cancer arises when genetic mutations occur, resulting in uncontrolled and dysregulated cellular proliferation. A basic understanding of the anatomy and physiology of genetics provides the foundation necessary to understand key concepts associated with precision medicine. Deoxyribonucleic acid, or DNA, is a molecule containing the specific biologic instructions that make each living organism unique and allow it to develop, survive, and replicate. During mitosis, a single parent cell divides; giving rise to two daughter cells, each containing its own complete copy of DNA. When not undergoing mitosis, various sections of DNA alternately open and close to facilitate the protein production essential for survival of the organism. Human DNA is composed of nucleotides made up of a sugar (deoxyribose), a phosphate group, and one of four bases – adenine (A), cytosine (C), guanine (G) and thymine (T). These nucleotides bind together in a ladder-like structure known as a double helix with the sugar and phosphate molecules alternating to form the ‘‘legs’’ of the ladder, and the bases pairing - A with T, and C with G - to form the rungs of the ladder. There are more than three billion base pairs in the entire sequence of human DNA; this complete set of genetic instructions is known as the human genome.3 The Human Genome Project, completed in 2003, mapped and sequenced the entire human genome and resulted in the rapid expansion of genomics, making possible research opportunities that may ultimately allow ‘‘medical science to develop highly effective diagnostic tools, to better understand the health needs of people based on

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their individual genetic make-ups, and to design new and highly effective treatments for disease.’’3 Except for a small amount of DNA found in the mitochondria within the cytoplasm, DNA is confined to the nucleus of the cell. To contain the DNA within the nucleus, it is tightly wound into 46 large molecular structures known as chromosomes. Contained within the chromosomes are 20,000 to 25,000 genes that are sections of DNA that code for proteins or segments of proteins.3,4 Despite the immense size of the human genome, genes account for only about 3% of the DNA contained within it. Large portions of chromosomes outside of the genes contain non-coding DNA, whose roles, though not completely understood, are to function as space holders and to regulate gene expression.4 Protein synthesis is accomplished through a complex and tightly regulated process involving both DNA and ribonucleic acid, or RNA. RNA is similar to DNA but, unlike DNA, it is a singlestranded molecule containing bases of adenine, cytosine, guanine, and uracil instead of thymine. While DNA orchestrates the production of proteins from its master code, it is through RNA that protein synthesis is actually accomplished. Contained within genes are codons that are specifically sequenced triplets of nucleotides that code for specific corresponding amino acids. There are 64 possible triplet combinations of the four bases that correspond to 20 possible amino acids. While some amino acids can be coded for by more than one triplet combination, each triplet codes for a single amino acid. One of the 64 triplets codes for the amino acid methionine, which communicates the message to initiate protein synthesis by translating RNA codons into amino acids. Sixty of the 64 triplets code for the remaining 19 amino acids, and three triplets communicate a stop message, indicating that amino acid production should cease. Just as there are segments of non-coding DNA contained outside of the genes, there are also non-coding segments of DNA interspersed within the coding segments of genes. Exons are the coding segments within genes and introns are the noncoding segments. Messenger RNA (mRNA) is formed in the nucleus of the cell as the complementary strand of a specific segment of DNA. Initially, it contains both introns and exons, but prior to leaving the nucleus, the introns are cleaved out so that only the critical, protein-coding segments of the mRNA enter the cytoplasm. Once in the cytoplasm,

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ribosomes and transfer RNA (tRNA) work together to synthesize proteins by stringing together amino acids in the specific sequences dictated by the codons. To foster faithful replication in daughter cells and to provide accurate direction to RNA from which to generate proteins, DNA within the cell nucleus must be accurately maintained without changes. Much like a treasured family recipe, it is tightly guarded because if the recipe becomes corrupted, any future copies of that recipe (analogous to the creation of daughter cells) will be incorrect and any attempts to make the recipe (analogous to the creation of proteins) may not result in a proper end product. Genetic Mutations Mutations are changes within DNA sequences that can take a variety of forms. The term wild type describes genes as they naturally occur, in the non-mutated form, and mutated is used to describe a gene that has altered genetic information. Germ line mutations are changes that occur in the DNA of sperm or egg cells and can be inherited from previous generations and passed on to future generations. Somatic (or acquired) mutations occur after conception and are changes that occur in non-germ cells (body cells that are not egg or sperm cells). Somatic mutations are neither inherited nor passed on to offspring. Daughter cells of the mutated somatic cell, however, will contain the mutation if the mutation is not corrected before the cell is able to replicate. Table 1 highlights the differences in germ line and somatic or acquired mutations.4 Point mutations involving an alteration in a single base pair can occur, as can deletions, translocations or insertions involving larger sections of DNA. Mutations can occur in coding or non-coding regions, within or outside of a gene. As mutations can take a variety of forms, the end results of mutations can also vary. The effects of point mutations, the most common type of DNA alteration, can be silent, particularly if they occur in a non-coding region or if the altered codon codes for the same amino acid as the original codon did. Missense point mutations occur when the new codon codes for a different amino acid, thus altering the resulting protein, and nonsense point mutations result from codon alterations that code a stop message resulting in a truncated protein. Although point mutations are not always problem-

TABLE 1. Characteristics of Germ Line and Somatic or Acquired Mutations4

Germ Line Mutations





Mutation is present in egg or sperm cells Mutation is passed on to offspring (heritable) Mutation is present in every cell of the offspring Associated with familial cancer syndromes (eg, familial adenomatous polyposis [APC gene mutations], breast and ovarian cancer [mutations in BRCA1 or BRCA2], ataxia telangiectasia associated with lymphoma [mutations in ATM gene])

Somatic or Acquired Mutations
Mutation occurs in cells other than egg or sperm cells (eg, lung or colon cells)
Mutation is not passed on to offspring (not heritable)
Mutation will be present in daughter cells of somatic cell with mutation if it is not corrected prior to the cell replicating

atic, depending on where they occur they can cause significant functional defects in the protein. Larger mutations, such as gene deletions or chromosome deletions, can be dramatic because they can result in the inability to produce proteins essential for cellular function and survival of the organism. Other mutations can cause gene amplification or copy number variation resulting in gene overexpression, and leading to the under- or overproduction of proteins needed for normal biologic function. Gene rearrangements can result in the production of abnormal proteins that are completely nonfunctional or disrupt normal function.4 In addition to genetic mutations, there are epigenetic alterations that can significantly impact gene expression. When epigenetic changes occur, the DNA is not mutated, but other conditions, such as abnormal methylation or histone changes, cause the genes to be over- or underexpressed. Genetics and Cancer Carcinogenesis (sometimes also referred to as oncogenesis or tumorigenesis) is the process

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by which normal cells become malignant. This normal-to-malignant transformation occurs as a multistep process during which environmental exposure and random-replication errors result in the accumulation of genetic mutations over time. The term oncogenic driver is used to describe mutations that confer a growth and survival advantage on tumor cells.5 The two most common oncogenic drivers are mutated proto-oncogenes and tumor suppressor genes. In normal cells, these genes work in concert to tightly regulate cell proliferation. Proto-oncogenes promote the cell’s forward movement through the cell cycle while tumor suppressor genes inhibit proliferation, especially when the cell contains defective DNA. Oncogenes, the mutated form of protooncogenes, are associated with a gain-offunction, that is, an increased ability to promote cellular growth and proliferation. Fusion oncogenes result from the aberrant combining of normal genes leading to the production of proteins that abnormally promote uncontrolled cell growth and proliferation. Two examples of fusion oncogenes are the breakpoint cluster region-Abelson (Bcr-Abl) oncogene in chronic myeloid leukemia and the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma receptor tyrosine kinase (EML4-ALK) in a sub-type of NSCLC. Unlike oncogenes, mutated tumor suppressor genes result in a loss of function, in that there is decreased ability to inhibit cell proliferation, even in the presence of defective DNA. The inability to prevent replication of cells containing defective DNA is a strong oncogenic driver. Of note, p53, a tumor suppressor gene, has been identified as the most frequently mutated gene associated with human cancers.6 Proto-oncogenes and tumor suppressor genes exert their effects on cellular activity through a variety of proteins that include growth factors, growth factor receptors, signal transduction proteins, transcription factors, cell-cycle control proteins, and DNA-repair proteins.7 These proteins are critical components of signal transduction pathways, which are the mechanisms by which extracellular stimuli are carried into the cell’s cytoplasm and nucleus, thereby influencing cellular activities including growth, proliferation, and survival. Events that occur earlier in the pathway (closer to the cell membrane) are considered to be ‘‘upstream,’’ while those occurring closer to the nucleus are considered to be ‘‘downstream.’’ Numerous pathways with significant re-

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dundancies exist, such that a single mutation is not sufficient to cause cancer. Activating mutations are mutations that cause proto-oncogenes to turn on, which can result in defective signaling pathways. These defects often result in a pathway that becomes constitutively turned on, generating downstream signals that promote cellular growth, survival, and proliferation in the absence of normal upstream stimuli.8 Some pathways that have been identified as altered in cancer include EGFR, HER2, KRAS, BRAF, ALK, and PI3K/AKT/mTOR. Table 2 identifies known altered pathways associated with specific cancers.8-10

IDENTIFICATION OF THERAPEUTIC TARGETS Increased understanding of the pathogenesis of cancer at the protein, genetic, and molecular levels informs the identification of clinically relevant biomarkers associated with particular cancers, possible actionable mutations and ideally, druggable (therapeutic) targets. The best targets are those that occur in cancer cells, but not in normal cells, because this minimizes the effects of treatment on non-cancer cells. Identifying actionable mutations, sometimes referred to as druggable targets, is key when trying to develop new treatment strategies. Actionable mutations include those genetic mutations that have been identified as oncogenic drivers and for which current therapies exist or are being investigated.9 Researchers are continuously trying to identify new and better targets for therapy. If a potential new target is identified, extensive and rigorous drug target validation must take place to assure a clear understanding of the role of the newly identified target in initiating or maintaining cancer. Rational drug development and selection takes into consideration the specific oncogenic driver of a given cancer and the manner in which the driving mutation manifests. For example, if a mutation results in the overexpression of a receptor located on the outside of a cell, a monoclonal antibody might be a reasonable therapeutic approach. Monoclonal antibodies are large proteins and, thus, unable to get inside the cell, but they are able to effectively bind to targets in the extracellular environment. The MAB could be specific for either the overexpressed receptor or the naturally occurring ligand that binds to the overexpressed receptor. In either situation, the naturally

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TABLE 2. Activating Mutations Associated with Specific Cancers8-10 Activating Mutation EGFR (Epidermal growth factor receptor) The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor. Binding of the protein to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. http://ghr.nlm.nih.gov/gene/EGFR HER2 The official name of this gene is ‘‘v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2.’’ The ERBB2 gene is also commonly referred to as Her-2/neu. This gene is one member of a family of genes that provide instructions for producing growth factor receptors. Growth factors are proteins that stimulate cell growth and division. http://ghr.nlm.nih.gov/gene/ERBB2 KRAS (Kirsten rat sarcoma viral oncogene homolog) The KRAS gene provides instructions for making a protein called K-Ras that is involved primarily in regulating cell division. As part of a signaling pathway known as the RAS/MAPK pathway, the protein relays signals from outside the cell to the cell’s nucleus. These signals instruct the cell to grow and divide or to mature and take on specialized functions (differentiate). The KRAS gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes: HRAS and NRAS. The proteins produced from these three genes are GTPases. These proteins play important roles in cell division, cell differentiation, and the self-destruction of cells (apoptosis). http://ghr.nlm.nih.gov/gene/KRAS BRAF (v-raf murine sarcoma viral oncogene homolog B) The BRAF gene provides instructions for making a protein that helps transmit chemical signals from outside the cell to the cell’s nucleus. This protein is part of a signaling pathway known as the RAS/MAPK pathway, which helps control several important cell functions. Specifically, the RAS/MAPK pathway regulates the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis). Chemical signaling through this pathway is essential for normal development before birth. http://ghr.nlm.nih.gov/gene/BRAF ALK (anaplastic lymphoma receptor tyrosine kinase) The ALK gene provides instructions for making a protein called anaplastic lymphoma kinase, part of a family of proteins called receptor tyrosine kinases (RTKs). Receptor tyrosine kinases transmit signals from the cell surface into the cell through a process called signal transduction. The process begins when the kinase is stimulated at the cell surface and then attaches to a similar kinase (dimerizes). After dimerization, the kinase is tagged with a marker called a phosphate group (a cluster of oxygen and phosphorus atoms) in a process called phosphorylation. Phosphorylation turns on (activates) the kinase. The activated kinase is able to transfer a phosphate group to another protein inside the cell, which is activated as a result. The activation continues through a series of proteins in a signaling pathway. These signaling pathways are important in many cellular processes such as cell growth and division (proliferation) or maturation (differentiation). Although the specific function of anaplastic lymphoma kinase is unknown, it is thought to act early in development to help regulate the proliferation of nerve cells. http://ghr. nlm.nih.gov/gene/ALK PI3k/AKT/mTOR ‘‘Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha.’’ PIK3CA is the gene’s official symbol. Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-

Cancer Type(s) Lung and colon cancers

Breast, ovarian, brain, stomach, and lung cancers

Pancreatic, lung, and colorectal cancers

Melanoma, and cancer of the colon and rectum, ovary, and thyroid

Neuroblastoma, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, and non–small cell lung cancer

PI3K - familial colorectal and breast cancers, cancers of the liver, lung ovary and stomach AKT - melanoma and glioma (Continued )

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TABLE 2. (Continued) Activating Mutation

Cancer Type(s)

phosphate) and PtdIns (4,5) P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS. http://ghr.nlm.nih.gov/gene/ PIK3CA mTOR (also called mammalian target of rapamycin) is a protein that helps control several cell functions, including cell division and survival, and binds to rapamycin and other drugs. mTOR may be more active in some types of cancer cells than it is in normal cells. Blocking mTOR may cause the cancer cells to die. It is a type of serine/ threonine protein kinase. http://www.cancer.gov/dictionary?CdrID¼653126

occurring ligand would be prevented from binding to the overexpressed receptor and would prevent the initiation of the signaling cascade. If, however, the mutation is manifesting as a constitutive intracellular stimulus for proliferation, blocking the receptor on the outside of the cell with a MAB will not stop the dysregulated proliferation. In this circumstance, it would be more reasonable to select a small molecule that can work outside the cell but also, as its name implies, is small enough to get inside the cell and effectively disrupt the aberrant signaling. Many small-molecule agents are kinase inhibitors, which work by blocking intracellular phosphorylation, an essential component of signaling pathways. Kinase inhibitors can target a single kinase for inhibition (eg, iressa targeting the intracellular tyrosine kinase domain of EGFR) or can be multitarget kinase inhibitors (eg, imatinib targeting Bcr-Abl, c-KIT, platelet derived growth factor [PDGF] and stem cell factor [SCF]). Most small-molecule agents inhibit tyrosine kinase activity, but newer agents have been developed that inhibit serine and threonine kinase activity (eg, vemurafinib and dabrafenib targeting v-raf murine sarcoma viral oncogene homolog B [BRAF]).

Intrinsic (primary) resistance and acquired resistance are also important considerations when developing and selecting therapeutics.11 Challenges associated with resistance can be exemplified using the example of mutations in the breakpoint cluster region-Abelson (Bcr-Abl) protein present in Philadelphia-chromosome–positive chronic myelogenous leukemia (CML). Imatinib mesylate is a first-generation tyrosine kinase inhibitor that specifically targets the Bcr-Abl fusion protein associated with CML. Despite the very precise action of imatinib mesylate on BcrAbl–positive cells, certain mutations in the BcrAbl protein resulted in primary resistance, and patients with those mutations never responded to therapy with imatinib mesylate. Additionally, other patients developed acquired Bcr-Abl mutations during treatment with imatinib mesylate, and despite an initial response, they ultimately lost their response to therapy. Second-generation Bcr-Abl agents have been developed that are able to successfully overcome most, but not all, of the imatinib mesylate-resistant Bcr-Abl mutations. Ongoing research is necessary to develop agents that can effectively overcome drug resistant mutations in CML and in other cancer types as well.

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PURSUING PRECISION: PREPARING FOR THE FUTURE With the completion of the sequencing of the human genome, the ability to identify genetic and ultimately molecular changes associated with cancer grew dramatically. Since the mapping of the human genome, many tumor genomes have been sequenced and specific genetic mutations associated with various cancers have been identified. The National Institutes of Health (NIH) has a goal to identify all genetic abnormalities associated with 50 major tumor types.12 Advances in technology have significantly decreased the time it takes to sequence a genome and the cost associated with sequencing. While it took 10 years to sequence the first genome, current technology allows for the sequencing of an entire genome in days.12 Additionally, in 2001, it cost 100 million dollars to sequence an entire genome. Today the cost is less than $10,000 and the NIH has a goal of reducing the cost to $1,000, thus making it feasible for patients to have their genomes and their tumor’s genome sequenced.12,13 Techniques have been developed that allow for whole exome sequencing, which involves sequencing just the coding regions of DNA. While whole genome sequencing and whole exome sequencing provide insight into the genetic directions for an organism, the developing field of proteomics, that is, the study of the structure, function, and interaction of proteins resulting from the genome, reveals the end products of the genetic code. For some time to come, our technological capabilities will far outpace our therapeutic capabilities leading to more questions than answers, but the ultimate goal is to identify the oncogenic drivers of each patient’s tumor, to have an available therapy targeting that specific driver, and to provide each patient with the precise therapy needed to effectively treat their cancer.

ETHICAL CONSIDERATIONS Having technology that outpaces therapeutic options, genetic information with uncertain implications and more questions than answers give rise to a number of ethical issues that must be addressed. Recognizing that sequencing the human genome touched on ethical as well as legal and social issues, monies were allocated to fund bioethical research in these areas.14 Areas of study

included privacy, confidentiality, and fairness in the use of genetic information. The Genetic Information Nondiscrimination Act of 2008 was passed to address some of the concerns about fairness in the use of genetic information.15 This law makes it illegal to base insurance eligibility or coverage decisions on genetic information. It also makes it illegal to base employment hiring or promotion decisions on genetic information. Concerns about the psychological impacts of genetic findings and implications for reproduction are sensitive topics that require further research and ongoing dialogue. Challenging clinical issues include informed consent, the need for genetic education for professionals, and the social risks and scientific limitations of the current state of knowledge of cancer and genetics. Is it reasonable to perform genetic testing if the implications of identified mutations are not known or if there are no treatments available for identified mutations? Do patients understand the implications for genetic testing? These issues will increasingly impact nurses and patients as we move further into a precision medicine approach to cancer care. The Oncology Nursing Society has provided guidance in the form of position papers addressing cancer genetics and genomics throughout the oncology care continuum, the role of the oncology nurse in cancer genetic counseling, and cancer predisposition genetic testing and risk assessment counseling.16 There is also a special interest group for cancer genetics that provides a forum for nurses to engage in dialogue about this important and rapidly evolving field.16

NURSING IMPLICATIONS The speed of progress and the large number of major developments related to precision medicine have created a steep learning curve for nurses as they fulfill their professional obligation to stay up to date with important trends and advances in oncology. This trend will not likely diminish in the foreseeable future as more continues to be learned about the presence and implications of genetic abnormalities associated with cancer. It is incumbent upon oncology nurses to understand the basic science underpinning these advances, to be able to verify that the medical therapy the physician ordered is appropriate given the molecular specifics of the patient’s tumor, and to educate the patient about his/her therapy. As new drugs that target specific genetic mutations become available, it is likely that they will be

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approved in conjunction with a companion diagnostic test to confirm the presence of the requisite target mutation. Keeping up to date on newly FDAapproved drugs will likely prove challenging, but the use of naming conventions for monoclonal antibodies and small molecules can help nurses to have a general knowledge about these new agents based on their generic names.17 Table 3 highlights key aspects of monoclonal antibodies and small molecules that can be ascertained from clues found in the generic name of the new agents.17

CONCLUSION Rapid progress in understanding the oncogenic drivers associated with cancer has been made

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possible by technological advances stemming from the sequencing of the human genome in 2003 and the subsequent sequencing of numerous cancer genomes. This expanded knowledge has led to a shift toward precision medicine where treatment is based on therapies that target specific genetic and epigenetic alterations associated with a particular cancer. An understanding of genetics, including normal and abnormal anatomy and physiology, will be necessary to provide quality care to patients with cancer in the precision medicine environment. As oncology nurses, our role in the management of patients with cancer is to provide safe, highquality care including education and support, and to advocate for the needs of patients with cancer, individually and collectively. By

TABLE 3. Monoclonal Antibodies and Small Molecule Agents: Clues to Key Aspects of Drugs Found in Generic Name17 Key Aspects of Drug Monoclonal antibodies






Large proteins that bind outside of a cell (too big to get inside) Given IV Potential for infusion reactions

Suffix of Generic Name of Drug mab ¼ monoclonal antibody mo ¼ mouse mo þ mab ¼ momab
100% mouse origin Example: ibritumomab tiuxetan xi ¼ chimeric, or a cross between mouse and human xi þ mab ¼ ximab
Approximately 90% human and 10% mouse origin Example: rituximab zu ¼ humanized zu þ mab ¼ zumab
96% to 97% human and 3% to 4% mouse origin Example: bevacizumab u ¼ fully human u þ mab ¼ umab
100% human Example: ofatumumab Where is the target for the monoclonal antibody located? tu ¼ tumor Example: rituximab ci ¼ cardiovascular Example: bevacizumab li or l ¼ immunomodulator Example: ipilimumab

Small molecules





Small enough to get inside the cell Usually oral agents – possible adherence issues and potential interactions with food or other drugs

ib ¼ internal binding Examples: lapatinib, pazopanib, and sorafenib

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embracing the paradigm shift to precision medicine, expending the effort necessary to learn the essential terminology, concepts, and principles, and working collaboratively with our physician

colleagues, we can best position our patients to maximize the potential that precision medicine can offer and thus, honor our commitment to our patients and to our profession.

REFERENCES 1. President’s Council of Advisors on Science and Technology. Priorities for personalized medicine. Washington, DC: President’s Council of Advisors on Science and Technology; 2008. 2. The National Academies Committee on A Framework for Developing a New Taxonomy of Disease – National Research Council. Toward precision medicine: building a knowledge network for biomedical research and a new taxonomy of disease. Washington, DC: The National Academies Press; 2011. 3. National Human Genome Research Institute. the human genome project completion: frequently asked questions, 2010. Available at: http://www.genome.gov/11006943. Accessed November 25, 2013. 4. National Cancer Institute, Understanding Cancer Series – Cancer Genomics. Available at: http://www.cancer.gov/ cancertopics/understandingcancer/cancergenomics/AllPages. Accessed November 25, 2013. 5. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature 2009;458:719-724. 6. Vogelstein B, Sur S, Prives C. P53: the most commonly altered gene in human cancer. Nature Education 2010;3:6. 7. Lodish H, Berk A, Zipursky SL, Matsudaiira P, Baltimore D, Darnell J. Molecular cell biology. 4th Ed. New York: W.H Freeman; 2000. 8. Musaffe T, Amos T. Activating mutations and targeted therapy in cancer. In: Cooper D, editor. Mutations in human genetic disease. 2012. Available at: http://www.intechopen.com/ books/mutations-in-human-genetic-disease/activating-mutationsand-targeted-therapy-in-cancer. Accessed November 25, 2013.

9. Mwenifumbo JC, Marra MA. Cancer genome –sequencing study design. Nature 2013;14:321-332. 10. Zahreddine H, Borden KLB. Mechanisms and insights into drug resistance in cancer. Front Pharmacol 2013;4:1-5. 11. National Institutes of Health. Human genome project fact sheet. National Institutes of Health. 2010. Available at: http:// report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid¼45&key¼H. Accessed November 25, 2013. 12. Wetterstrand KA. DNA sequencing costs: data from the NHGRI genome sequencing program (GSP). Available at: http://www.genome.gov/sequencingcosts. Accessed November 25, 2013. 13. Human Genome Project. Archive: Ethical, legal and social issues. Available at: http://web.ornl.gov/sci/techresources/ Human_Genome/elsi/index.shtml. Accessed November 25, 2013. 14. Human Genome Project. Genetic information nondiscrimination act 2008. Available at: http://www.genome.gov/ 10002328. Accessed November 25, 2013. 15. Oncology Nursing Society, Genetics. Available at: http:// www.ons.org/ClinicalResources/Genetics. Accessed November 25, 2013. 16. American Medical Association. Monoclonal antibodies. Available at: http://www.ama-assn.org/ama/pub/physicianresources/medical-science/united-states-adopted-names-council/ naming-guidelines/naming-biologics/monoclonal-antibodies. page. Accessed November 25, 2013. 17. Genetics Home Reference. Genes. Available at: http:// ghr.nlm.nih.gov/BrowseGenes. Accessed November 25, 2013.

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APPENDIX A Glossary Activating mutation – Mutations which activate proto-oncogenes. Musaffe T, Amos CI (2012). Activating Mutations and Targeted Therapy in Cancer, Mutations in Human Genetic Disease, Prof. David Cooper (Ed.), ISBN: 978-953-51-0790-3, InTech, http://dx.doi.org/10.5772/48701. Available at: http://www.intechopen.com/books/mutations-inhuman-genetic-disease/activating-mutations-andtargeted-therapy-in-cancer Actionable mutation – Biological molecules or processes that can be targeted by an existing or experimental drug. Mwenifumbo JC, Marra MA. Cancer genome sequencing study design. Nature 2013;14:321-332. Acquired resistance – A resistance to therapy that develops after exposure to drug treatment. Zahreddine H. Borden KLB. Mechanisms and insights into drug resistance in cancer. Frontiers Pharmacol 2013;4:1-5. Biomarker – A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition. Also called molecular marker and signature molecule. http://www.cancer.gov/ dictionary?CdrID¼45618 Carcinogenesis – The process by which normal cells are transformed into cancer cells. http:// www.cancer.gov/dictionary?CdrID¼46487, the process of initiating and promoting cancer Mosby’s Medical Dictionary. 8th ed. Elsevier, 2009, Available at: http://medical-dictionary. thefreedictionary.com/tumorigenesis. Chromosome – An organized package of DNA found in the nucleus of the cell. Different organisms have different numbers of chromosomes. Humans have 23 pairs of chromosomes–22 pairs of numbered chromosomes, called autosomes, and one pair of sex chromosomes, X and Y. Each parent contributes one chromosome to each pair so that offspring get half of their chromosomes from their mother and half from their father. http://www. genome.gov/glossary/index.cfm?id¼33 Codons – Trinucleotide sequences of DNA or RNA that corresponds to specific amino acids. The genetic code describes the relationship between the sequence of DNA bases (A, C, G, and

T) in a gene and the corresponding protein sequence that it encodes. The cell reads the sequence of the gene in groups of three bases. There are 64 different codons: 61 specify amino acids while the remaining three are used as stop signals. http://www.genome.gov/Glossary/index. cfm?id¼36 Companion diagnostic test – A test that is carried out specifically to assist physicians to make a treatment decision. When a medication’s potential benefit is directly related to the presence or absence of a specific mutation, a companion diagnostic test would identify whether or not the patient had the pertinent mutation and the patient would or would not receive the medication based on the test result. For example, the drug crizotinib is only indicated for patients whose non-small cell lung cancer is associated with an ALK gene rearrangement. A companion diagnostic test would specifically test for the presence or absence of the ALK gene rearrangement and treatment with crizotinib would only be indicated if the patient’s tumor was positive for this mutation. Copy number variation (CNV) – When the number of copies of a particular gene varies from one individual to the next. Following the completion of the Human Genome Project, it became apparent that the genome experiences gains and losses of genetic material. The extent to which copy number variation contributes to human disease is not yet known. It has long been recognized that some cancers are associated with elevated copy numbers of particular genes. http://www. genome.gov/Glossary/index.cfm?id¼40 Deoxyribonucleic acid (DNA) – The chemical name for the molecule that carries genetic instructions in all living things. The DNA molecule consists of two strands that wind around one another to form a shape known as a double helix. Each strand has a backbone made of alternating sugar (deoxyribose) and phosphate groups. Attached to each sugar is one of four bases– adenine (A), cytosine (C), guanine (G), and thymine (T). The two strands are held together by bonds between the bases; adenine bonds with thymine, and cytosine bonds with guanine. The sequence of the bases along the backbones serves as instructions for assembling protein and RNA

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molecules. http://www.genome.gov/Glossary/ index.cfm?id¼48 Drug target validation – The process researchers use after discovering a potentiallyvulnerable molecule involved in a cancer process or pathway to show that they understand how the pathway or process actually works in cancer cells. If researchers are able to validate the target, they work to design new therapies to disrupt its activity with great precision. http://www.cancer.gov/ cancertopics/understandingcancer/targetedtherapies/ htmlcourse/page1/AllPages#b Druggable targets – A protein class that has had drugs developed against it. Examples - cell receptors, ion channels, enzymes (eg, COX-2). Segen’s Medical Dictionary, 2012. http://www.medicaldictionary.thefreedictionary.com/DruggableþTarget Epigenetic alterations – A heritable change that does not affect the DNA sequence but results in a change in gene expression. Examples include promoter methylation and histone modifications. http://www.cancer.gov/ geneticsdictionary?search¼epigenetic Exon – The portion of a gene that codes for amino acids. In the cells of plants and animals, most gene sequences are broken up by one or more DNA sequences called introns. The parts of the gene sequence that are expressed in the protein are called exons, because they are expressed, while the parts of the gene sequence that are not expressed in the protein are called introns, because they come in between–or interfere with–the exons. http://www.genome.gov/ Glossary/index.cfm?id¼61 First generation (drugs) – Drugs that are the first of their kind achieving a desired therapeutic effect. Subsequent generations are often variations of first generation agents and generally offer improvements and address problematic aspects associated with the first generation. Fusion (onco) gene – A gene made by joining parts of two different genes. Fusion genes may occur naturally in the body by transfer of DNA between chromosomes. For example, the BCR-ABL gene found in some types of leukemia is a fusion gene. Fusion genes can also be made in the laboratory by combining genes or parts of genes from the same or different organisms. http://www.cancer. gov/dictionary?CdrID¼613509 Gene – The basic physical unit of inheritance. Genes are passed from parents to offspring and contain the information needed to specify traits. Genes are arranged, one after another, on struc-

tures called chromosomes. A chromosome contains a single, long DNA molecule, only a portion of which corresponds to a single gene. Humans have approximately 20,000 genes arranged on their chromosomes. http://www.genome.gov/ Glossary/index.cfm?id¼70 Gene amplification – An increase in the number of copies of a gene. There may also be an increase in the RNA and protein made from that gene. Gene amplification is common in cancer cells, and some amplified genes may cause cancer cells to grow or become resistant to anticancer drugs. Genes may also be amplified in the laboratory for research purposes. http://www.cancer.gov/dictionary?CdrID ¼650175 Gene deletion - The loss of all or a part of a gene. There may also be a change in the RNA and protein made from that gene. Certain gene deletions are found in cancer and in other genetic diseases and abnormalities. http://www.cancer.gov/ dictionary?CdrID¼46390 Gene over-expression – To make too many copies of a protein or other substance. Overexpression of certain proteins or other substances may play a role in cancer development. http:// www.cancer.gov/dictionary?cdrid¼45812 Genetic – Of, relating to, or involving genes. http://www.merriam-webster.com/dictionary/genetic Genetics – The study of inheritance patterns of specific traits. http://web.ornl.gov/sci/ techresources/Human_Genome/glossary.shtml#G The study of genes and heredity. Heredity is the passing of genetic information and traits (such as eye color and an increased chance of getting a certain disease) from parents to offspring. http:// www.cancer.gov/dictionary Genome – The entire set of genetic instructions found in a cell. In humans, the genome consists of 23 pairs of chromosomes, found in the nucleus, as well as a small chromosome found in the cells’ mitochondria. These chromosomes, taken together, contain approximately 3.1 billion bases of DNA sequence. http://www.genome.gov/ Glossary/index.cfm?id¼90 http://www.genome. gov/Glossary/index.cfm?id¼90 Genomics – The study of genes and their function. http://web.ornl.gov/sci/techresources/ Human_Genome/glossary.shtml#G Germ line mutations – A gene change in a body’s reproductive cell (egg or sperm) that becomes incorporated into the DNA of every cell in the body of the offspring. Germ line mutations are passed on from parents to offspring. Also

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called hereditary mutation. http://www.cancer.gov/ dictionary?CdrID¼46384 Intrinsic resistance – A resistance to therapy existing prior to the initiation of drug treatment. Zahreddine H, Borden KLB. Mechanisms and insights into drug resistance in cancer. Frontiers in Pharmacology 2013;4:1-5. Intron – A portion of a gene that does not code for amino acids. In the cells of plants and animals, most gene sequences are broken up by one or more introns. The parts of the gene sequence that are expressed in the protein are called exons, because they are expressed, while the parts of the gene sequence that are not expressed in the protein are called introns, because they come in between the exons. http://www.genome.gov/ Glossary/index.cfm?id¼113 Kinase inhibitors – Substances that blocks the action of enzymes called kinases. Tyrosine, serine and threonine kinases are a part of many cell functions, including cell signaling, growth, and division. These enzymes may be too active or found at high levels in some types of cancer cells, and blocking them may help keep cancer cells from growing. Some kinase inhibitors are used to treat cancer. They are a type of targeted therapy. http://www.cancer.gov/dictionary Messenger Ribonucleic Acid (mRNA) – A singlestranded RNA molecule that is complementary to one of the DNA strands of a gene. The mRNA is an RNA version of the gene that leaves the cell nucleus and moves to the cytoplasm where proteins are made. During protein synthesis, an organelle called a ribosome moves along the mRNA, reads its base sequence, and uses the genetic code to translate each three-base triplet, or codon, into its corresponding amino acid. http://www.genome.gov/ Glossary/index.cfm?id¼123 Monoclonal antibodies – A type of protein made in the laboratory that can bind to substances in the body, including cancer cells. There are many kinds of monoclonal antibodies. A monoclonal antibody is made so that it binds to only one substance. Monoclonal antibodies are being used to treat some types of cancer. They can be used alone or to carry drugs, toxins, or radioactive substances directly to cancer cells. http://www. cancer.gov/dictionary?cdrid¼46066 Most monoclonal antibodies cannot penetrate the cell’s plasma membrane and are directed against targets that are outside cells or on the cell surface. http:// www.cancer.gov/cancertopics/factsheet/Therapy/ targeted

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Multi-target inhibition – Therapeutic agents with more than one target such as the multitarget tyrosine kinase inhibitor imatinib which targets Bcr-Abl, c-KIT, platelet derived growth factor (PDGF) and stem cell factor (SCF). Mutations – Changes in a DNA sequence. Mutations can result from DNA copying mistakes made during cell division, exposure to ionizing radiation, exposure to chemicals called mutagens, or infection by viruses. Germ line mutations occur in the eggs and sperm and can be passed on to offspring, while somatic mutations occur in body cells and are not passed on. http://www.genome. gov/glossary/index.cfm?id¼134 Non-coding DNA – DNA sequences that do not code for amino acids. Most non-coding DNA lies between genes on the chromosome and has no known function. Other non-coding DNA, called introns, is found within genes. Some non-coding DNA plays a role in the regulation of gene expression. http://www.genome.gov/Glossary/index.cfm? id¼137 Oncogene – A gene that is a mutated (changed) form of a gene involved in normal cell growth. Oncogenes may cause the growth of cancer cells. Mutations in genes that become oncogenes can be inherited or caused by being exposed to substances in the environment that cause cancer. http://www.cancer.gov/dictionary?CdrID¼46259 Oncogenesis – The process of initiating and promoting the development of a neoplasm through the action of biologic, chemical, or physical agents. Mosby’s Medical Dictionary. 8th ed. Elsevier, 2009. Available at: http://medical-dictionary. thefreedictionary.com/tumorigenesis. Oncogenic driver – A mutation that is causally implicated in oncogenesis. It has conferred growth advantage on the cancer cell and has been positively selected in the microenvironment of the tissue in which the cancer arises. Stratton MR, Campbell PJ, Futreal PA. The Cancer Genome. Nature Rev 2009;45:719-724. Personalized medicine – A form of medicine that uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease. In cancer, personalized medicine uses specific information about a person’s tumor to help diagnose, plan treatment, find out how well treatment is working, or make a prognosis. Examples of personalized medicine include using targeted therapies to treat specific types of cancer cells, such as HER2-positive breast cancer cells, or using tumor marker testing to help diagnose

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cancer. Also called precision medicine. http:// www.cancer.gov/dictionary?CdrID¼561717 Point mutations – Mutations when a single base pair is altered. Point mutations can have one of three effects. First, the base substitution can be a silent mutation where the altered codon corresponds to the same amino acid. Second, the base substitution can be a missense mutation where the altered codon corresponds to a different amino acid. Or third, the base substitution can be a nonsense mutation where the altered codon corresponds to a stop signal. http://www.genome.gov/ glossary/index.cfm?id¼156 Precision medicine – Refers to the tailoring of medical treatment to the individual characteristics of each patient. It does not literally mean the creation of drugs or medical devices that are unique to a patient, but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology and/or prognosis of those diseases they may develop, or in their response to a specific treatment. Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not. Although the term ‘‘personalized medicine’’ is also used to convey this meaning, that term is sometimes misinterpreted as implying that unique treatments can be designed for each individual. For this reason, the Committee on a Framework for Developing a New Taxonomy of Disease thinks that the term ‘‘precision medicine’’ is preferable to ‘‘personalized medicine’’ to convey the meaning intended in this report. It should be emphasized that in ‘‘precision medicine’’ the word ‘‘precision’’ is being used in a colloquial sense, to mean both ‘‘accurate’’ and ‘‘precise’’ (in the scientific method, the accuracy of a measurement system is the degree of closeness of measurements of a quantity to that quantity’s actual (true) value whereas the precision of a measurement system, also called reproducibility or repeatability, is the degree to which repeated measurements under unchanged conditions show the same results) The National Academies Committee on A Framework for Developing a New Taxonomy of Disease – National Research Council. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease. Washington, DC: The National Academies Press; 2011, p. 125. Predictive biomarker – A type of biomarker that provides information on the effect of a

therapeutic intervention. A predictive biomarker can also be a target for therapy. Oldenhuis, CNAM, Oosting, SF, Gietema, JA, de Vries EGE, Prognostic versus predictive value of biomarkers in oncology. European Journal of Cancer 2008;44:946-953. Prognostic biomarker – A type of biomarker that provides information about the patient’s overall cancer outcome, regardless of therapy. Oldenhuis CNAM, Oosting SF, Gietema JA, de Vries EGE, Prognostic versus predictive value of biomarkers in oncology. European Journal of Cancer 2008;44:946-953. Proteomics – The study of the full set of proteins encoded by a genome. http://web.ornl.gov/sci/ techresources/Human_Genome/glossary.shtml#P The study of the structure and function of proteins, including the way they work and interact with each other inside cells. http://www.cancer. gov/dictionary?CdrID¼306524 Rearrangements (gene) – A structural alteration in a chromosome, usually involving breakage and reattachment of a segment of chromosome material, resulting in an abnormal configuration; examples include inversion and translocation. http://ghr.nlm.nih.gov/glossary¼rearrangement Ribonucleic acid (RNA) – One of two types of genetic material found in all living cells and many viruses. (The other type of genetic material is DNA.) There are several types of ribonucleic acid (RNA). RNA plays important roles in protein synthesis and other cell activities. http://aidsinfo. nih.gov/education-materials/glossary/637/ribonucleicacid Second generation (drugs) – Drugs that have the same desired effect as first-generation agents but improved or changed in some substantial way, second generation agents are often designed to overcome problems associated with first generation agents, such as resistance. Zahreddine, H. & Borden K.L.B. Mechanisms and insights into drug resistance in cancer. Frontiers Pharmacol 2013;4:1-5. Signal transduction – The process by which a cell responds to substances in its environment. The binding of a substance to a molecule on the surface of a cell causes signals to be passed from one molecule to another inside the cell. These signals can affect many functions of the cell, including cell division and cell death. Cells that have permanent changes in signal transduction molecules may develop into cancer. http://www. cancer.gov/dictionary?CdrID¼46657

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Small molecule (agents) – A type of targeted therapy that can easily travel across cell membranes, including the plasma membrane. This means that they can be used to interfere with proteins located either outside or inside the cell. Small molecules are often designed to interact with specific areas of the target protein in order to modify its enzyme activity or its interaction with other molecules. http://www.cancer.gov/ cancertopics/understandingcancer/targetedtherapies/ htmlcourse/page1/AllPages#b Somatic mutations (somatic cell genetic mutations)- Changes in the genetic structure that are neither inherited nor passed to offspring. Also called acquired mutations. http://web. ornl.gov/sci/techresources/Human_Genome/glossary. shtml#S Targeted therapies – Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. Because scientists often call these molecules ‘‘molecular targets,’’ targeted cancer therapies are sometimes called ‘‘molecularly targeted drugs,’’ ‘‘molecularly targeted therapies,’’ or other similar names. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than other types of treatment, including chemotherapy and radiotherapy, and less harmful to normal cells. http://www.cancer.gov/ cancertopics/factsheet/Therapy/targeted

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Transfer ribonucleic acid (tRNA) – A small RNA molecule that participates in protein synthesis. Each tRNA molecule has two important areas: a trinucleotide region called the anticodon and a region for attaching a specific amino acid. During translation, each time an amino acid is added to the growing chain, a tRNA molecule forms base pairs with its complementary sequence on the messenger RNA (mRNA) molecule, ensuring that the appropriate amino acid is inserted into the protein. http://www.genome.gov/Glossary/index. cfm?id¼198 Tumor suppressor gene – A type of gene that makes a protein called a tumor suppressor protein that helps control cell growth. Mutations (changes in DNA) in tumor suppressor genes may lead to cancer. Also called antioncogene. http://www. cancer.gov/dictionary?CdrID¼46657 Tumorigenesis – The process of initiating and promoting the development of a tumor. Mosby’s Medical Dictionary. 8th ed. Elsevier, 2009. http://medical-dictionary.thefreedictionary. com/tumorigenesis. Wild type gene – The normal, as opposed to the mutant, gene. http://ghr.nlm.nih.gov/glossary¼ wildtypeallele Whole exome sequencing – Identifying the order of all the protein coding regions (exons) of the DNA. Whole genome sequencing – Identifying the order of the entire length of DNA including introns and exons, coding and non-coding regions.