Cancer Molecular Profiling - Leukemia & Lymphoma Society

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Cancer Molecular ProfilingNo. 31 in a series providing the latest information forpatients, caregivers and healthcare Information Specialist: 800.955.4572There is a list of definitions on page 4. These words areitalicized at first mention throughout the text.Highlightsl olecular profiling uses various technologies toMidentify cancer biomarkers; the findings informdoctors of the probability that cancers will be sensitiveor resistant to treatment.l A cancerbiomarker is associated with the presence ofcancer in the body. A biomarker can be produced bythe tumor itself, or it may be a specific response by thebody to the presence of cancer.l Examplesof molecular profiling technologiesinclude immunohistochemistry (IHC), fluorescencein situ hybridization (FISH), next-generationsequencing (NGS) and quantitative polymerasechain reaction (qPCR).l Precisionmedicine, also called “personalizedmedicine,” uses information about a person’s lifestyle,environment and biology to prevent, diagnose andtreat diseases.l Thegoal of precision medicine is to understand therelevant characteristics related to a particular diseaseand then to tailor therapy to that disease.IntroductionCancer is a result of an uncontrolled growth of abnormal cells,driven by genetic (molecular) changes that are either acquiredor inherited from our parents. Each cancer has a uniqueset of molecular changes in the cancer cells. Technologicaldevelopments have made a molecular profiling analysispossible; this allows doctors to distinguish the moleculardifferences between cancer cells and healthy cells.Molecular test findings provide doctors with the informationthey need to review what genes have been changed (mutated).By identifying these mutations, your doctor can figure out ifone treatment may work better than another for you.Support for this publication provided byIt is now possible to identify unique combinations of tumorspecific biomarkers that can help in the diagnosis, prognosis(likely outcome) and treatment of cancer. The type andnumber of mutations may predict how a patient will respondto a specific drug. The ultimate goal of molecular profilingis the development of individualized, highly targeted andeffective therapies that can improve patient outcomes.Molecular ProfilingMolecular profiling involves the use of various technologiesto understand the underlying characteristics that are foundin cancer cells. Biomarkers are molecules that show eithernormal or abnormal signs or processes in the body; abnormalsigns could indicate disease. Molecular profiling can be usedto identify specific cancer biomarkers that are associated withresponse, resistance or lack of response to certain treatmentapproaches. This information can lead to the development oftargeted therapies which are designed to be more effective fora specific tumor profile (a “profile” is information about thegenes within cancer cells).How Molecular Profiling Works. Molecular profilingidentifies the specific DNA (deoxyribonucleic acid), RNA(ribonucleic acid), or protein molecule that is associated witha disorder. First, a biopsy procedure obtains a patient’s samplefrom a tumor tissue; bone marrow; lymph node (for someblood cancers); or peripheral blood, in cases where tumorcells are circulating. The sample is sent to a laboratory, whereit undergoes various molecular profiling tests to identify theunique biomarkers that correspond to the patient’s cancer.These are some methods currently used for tumor profiling.(IHC) —This lab test usesantibodies to detect certain antigens (markers) in a tissuesample acquired from a biopsy. When the antibodies bind tothe antigen in the tissue sample, fluorescent dyes or enzymeslinked to the antibodies are activated and the antigen can beseen under a microscope. Immunohistochemistry providesinformation that helps doctors to diagnose diseases such ascancer. It may also be used to distinguish between differenttypes of cancer. A test called “flow cytometry” uses the sameprinciples, except that it is performed on a suspension of cellsin a liquid, rather than on cells embedded in a tissue sample. ImmunohistochemistryFS31 Cancer Molecular Profiling I page 1January 2018

Cancer Molecular ProfilingNext-Generation Sequencing (NGS)—This term describesa number of different sequencing technologies. NGS testsrapidly examine stretches of DNA or RNA. They detectDNA mutations, copy number variations and gene fusionsacross the genome and provide information about prognosisand treatment.Fluorescence in situ Hybridization (FISH)—This laboratorytechnique is used to evaluate genes and/or DNA sequences onchromosomes. Cells and tissue are removed using blood ormarrow tests. In the laboratory, a fluorescent dye is added tosegments of the DNA; the modified DNA is added to cellsor tissues on a glass slide. When these pieces of DNA bindto specific genes or areas of chromosomes on the slide, they“glow” when viewed under a microscope that has a speciallight. In this way, portions of chromosomes that are eitherincreased or decreased in number, or are rearranged, can beidentified. FISH can be helpful in diagnosing, assessing riskand treatment needs, as well as for monitoring treatmenteffectiveness.Quantitative Polymerase Chain Reaction (qPCR)— Thisis a technique that expands trace amounts of DNA so that aspecific segment of DNA can be studied. This technique hasbecome useful in detecting a very low concentration of bloodcancer cells, too few to be seen using a microscope. A testusing qPCR can detect the presence of a single blood cancercell among 100,000 to 1,000,000 healthy blood cells. Apatient’s blood or bone marrow is used for this test.FS31 Cancer Molecular Profiling I page 2

Cancer Molecular ProfilingCancer Biomarkers. Biomarkers are molecules thatindicate either a normal or an abnormal process in the body;abnormal signs, substances, or processes may indicate anunderlying disease or condition. Several types of molecules—including DNA, proteins, or RNA—can be used asbiomarkers. Biomarkers are produced by the cancer tissueitself or by other cells in the body that may be respondingto cancer. Biomarkers may be found in the blood, urine,stool, and cancer tissue, as well as in other tissues and bodilyfluids. Biomarkers are not limited to indicating cancer. Thereare biomarkers for other conditions, such as heart disease,multiple sclerosis and many other diseases. (Biomarkers arealso known as “molecular markers.”)There are many types of cancer biomarkers. Depending onthe particular characteristics of the molecule, biomarkerscan have different functions and can react in specific ways tocertain treatments. Biomarkers can bemarkers—A large group of molecular testscan provide information that helps in the diagnosis orclassification of a particular disease. An example of adiagnostic marker is the presence of the “Philadelphiachromosome" in chronic myeloid leukemia.l Diagnosticmarkers—These biomarkers help thedoctor determine likely patient outcomes, such asl Prognosticoverall survival. An example of a prognostic marker isthe presence of TP53 mutations (the most commonlymutated gene in people who have cancer). The presenceof a TP53 mutation identifies patients who are likely tohave a more aggressive disease course, regardless of thetreatment used in most cases.markers—These biomarkers are used tohelp doctors tailor treatment decisions to a particularpatient. They can predict the activity of a specific type oftherapy. They indicate the potential benefit of a specifictreatment for the intended patient. An example is theeffectiveness of lenalidomide (Revlimid ) in patients withmyelodysplastic syndromes (MDSs) who have the del(5q)mutation. Patients with the del(5q) mutation have shownimproved outcomes when treated with lenalidomide.l PredictiveImplications for Targeted Therapy:Precision MedicinePrecision medicine, also known as “personalized medicine,”is defined by the National Cancer Institute as “a form ofmedicine that uses information about a person’s genes,proteins, and environment to prevent, diagnose and treatdisease.” Precision medicine emerged within the last 20 yearsas a result of the development and refinement of molecularBiomarkers Significant for Study and Treatment of Hematologic CancersChromosome and GeneAbbreviationsAssociated CancerTreatment CorrelationPhiladelphia chromosomet(9;22) (translocationbetween chromosomes 9 22)Chronic myeloid leukemia (CML), acutelymphoblastic leukemia (ALL)Responds to imatinib (Gleevec ), dasatinib (Sprycel ),nilotinib (Tasigna )IDH2 (R140 or R172)Acute myeloid leukemia (AML)Responds to enasidenib (Idhifa )JAK2 V617FMyeloproliferative neoplasms (MPNs):polycythemia vera (PV), myelofibrosis (MF),essential thrombocythemia (ET) **Responds to ruxolitinib (Jakafi )PML-RARAAcute promyelocytic leukemia (APL)Responds to all-trans retinoic acid (ATRA), arsenictrioxide (Trisenox )FLT3-ITDAcute myeloid leukemia (AML)Responds to midostaurin (Rydapt )ALK rearrangementAnaplastic large-cell lymphoma (ALCL)Responds to crizotinib (Xalkori )*BRAF V600EHairy cell leukemiaResponds to vemurafenib (Zelboraf )**This drug is not FDA approved for this indication.**Use of ruxolitinib for this diagnosis has not been FDA approved.Table 1. This table lists some of the biomarkers that are currently known to be significant for the study and treatment of hematologic cancers.FS31 Cancer Molecular Profiling I page 3

Cancer Molecular Profilingtechniques. While cytotoxic agents (drugs that are toxic tocells) destroy rapidly dividing cells by disrupting DNA andmechanisms of cell division, molecularly-targeted therapiescontrol the function of specific molecular targets in thesignaling, proliferation, metabolism and death of When you have this conversation with your healthcareprovider(s), the following questions may be useful.Most tumors have multiple mutations, rather than justthe one or two mutations originally suspected. This is animportant discovery in recent years and it explains whytherapies designed to target a single mutation may notbe fully effective. Now, the challenge for researchers anddoctors is to utilize the information that molecular profilingprovides, and determine its implications for targetedtherapy. Targeted therapies can be more effective, causefewer side effects, and have a better chance to cure, or atleast effectively manage, a disease.l CanCurrent research strategies aim tol Matchthe individual genetic profile of tumor cells (andpatients) with therapies that have been designed toaddress this complexityl Includeseveral molecularly targeted agents in the sameprotocol. Patients are assigned to a specific agent based onthe molecular abnormalities identified in their tumors.In some cancers, molecular profiling has been instrumental inidentifying factors that have led to noteworthy improvementsin survival rates. They includel A current understanding of the molecular features oftumorsl Thedevelopment of diagnostic technologies that identifypatient biomarkersl Moderndrug development that enables targeting ofeither specific biomarkers or cellular mechanisms.The Cancer Genome Atlas (TCGA). This project,established by the National Institutes of Health (NIH),is designed to generate comprehensive maps of essentialgenomic changes in the major types and subtypes of cancer.The Cancer Genome Atlas was designed to be a resource forgroundbreaking research aimed at developing better strategiesfor preventing, diagnosing and treating cancer. The CancerGenome Atlas also serves as a model for other genomemapping projects.Questions for Your Treatment TeamMolecular profiling may be neither applicable nor availableto every patient or for every cancer diagnosis. Patients shoulddiscuss with the members of their treatment team whether ornot molecular profiling is a good option for their particularQuestions to ask about molecular profiling:l Ismy tumor/cancer eligible for molecular profiling?I have molecular profiling if I have already receivedtreatment?l Whatare the benefits of molecular profiling for myspecific cancer?l Whatbiomarkers are generally associated with my cancer?l Whatcould molecular profiling or biomarker analysis tellme about my specific cancer?l WillI need any additional testing? If so, what typeof tests?l Howcostly is molecular profiling? Will the testing becovered by my insurance provider? Is there financialassistance available?l Whowill perform my molecular profiling analysis?Where will it be performed?l Howlong will it take to get results?l Howwill you use the results of my molecular profilinganalysis?l Howlikely is it that molecular profiling could identify atargeted treatment for my type of cancer?l Whathappens if molecular profiling identifies aprescription drug that would be considered “off-label”use, but that may be an effective treatment for me?l WillI ever need to get another molecular profile done forthis diagnosis? What if I develop a different form of cancer?DefinitionsAntibody. A type of protein created by plasma cells (whiteblood cells) when they encounter bacteria, viruses, or othertriggers called “antigens” that the body senses as foreign.Antibodies help the body fight against invaders that makepeople sick. Antibodies can also be made in a lab.Antigen. A substance that creates a response when itencounters cells of the immune system. Examples of antigensare bacteria, viruses, toxins (poisons), chemicals and allergens.Body tissues and cells, including cancer cells, also carry antigensthat can cause an immune response. Antigens stimulate T cellsto respond, and plasma cells to produce antibodies.Biomarker. A molecule found in blood or tissues thatis a sign of either a normal or an abnormal process, or ofFS31 Cancer Molecular Profiling I page 4

Cancer Molecular Profilinga condition or disease. A biomarker may be used to seehow well the body responds to a treatment for a disease orcondition.Copy number variations. Sections of the genome thatare repeated. The number of times they are repeated variesfrom person to person as well as between some tumor cellsand normal cells.Cytotoxic. Toxic (harmful or poisonous) to living cells.DNA sequencing. The process of determining the preciseorder of nucleotides (which form the basic structural unit ofDNA) within a DNA molecule.Genetic markers. A gene or short sequence of DNA usedto identify a chromosome, or to locate other genes on agenetic map.Genome. The complete set of either genes or geneticmaterial present in a cell or an organism (an “organism”could be a person).Molecular diagnosis. The process of identifying a diseaseby studying molecules, such as proteins, DNA and RNA, ina tissue or fluid.Molecular profiling. Various technologies used to identifycancer biomarkers associated with either the response or theresistance to certain treatments. The information gatheredis used to identify and create targeted therapies designed towork better for a specific cancer or tumor profile.Overexpression. Too many copies of a protein or othersubstance are being made.Precision medicine (personalized medicine). Thistype of treatment uses information about a person’s lifestyle,environment, and biology to prevent, diagnose and treatdiseases.AcknowledgementLLS gratefully acknowledgesTimothy Graubert, MDDirector, Hematologic Malignancies ProgramHagler Family Chair in OncologyMassachusetts General Hospital Cancer CenterProfessor of Medicine, Harvard Medical SchoolBoston, MAfor his review of Cancer Molecular Profiling and for his importantcontributions to the material presented in this publication.We’re Here to HelpLLS is the world’s largest voluntary health organizationdedicated to funding blood cancer research, education andpatient services. LLS has chapters throughout the UnitedStates and in Canada. To find the chapter nearest to you, visitour Web site at or contactThe Leukemia & Lymphoma Society3 International Drive, Suite 200Rye Brook, NY 10573Contact an Information Specialist at (800) 955-4572Email: infocenter@LLS.orgLLS offers free information and services for patients andfamilies touched by blood cancers. The following entries listvarious resources available to you. Use this information tolearn more, to ask questions, and to make the most of yourhealthcare team.Consult with an Information Specialist. InformationSpecialists are master’s level oncology social workers, nursesand health educators. They offer up-to-date disease andtreatment information. Language services are available. Formore information, pleasel Call:(800) 955-4572 (M-F, from 9 am to 9 pm EST)l Email:l Liveinfocenter@LLS.orgchat: Information Booklets. LLS offers free education andsupport booklets that can either be read online or ordered.For more information, please visitón en Español (LLS information in Spanish).For more information, please visit Education Programs. LLS offersfree telephone/Web and video education programs forpatients, caregivers and healthcare professionals. For moreinformation, please visit Community. The one-stop virtual meeting place fortalking with other patients and receiving the latest bloodcancer resources and information. Share your experienceswith other patients and caregivers and get personalizedsupport from trained LLS staff. To join, Online Chats. Moderated online chats canprovide support and help cancer patients to reach out andshare information. To join, please visit Cancer Molecular Profiling I page 5

Cancer Molecular ProfilingLLS Chapters. LLS offers support and services in theUnited States and Canada including the Patti RobinsonKaufmann First Connection Program (a peer-to-peer supportprogram), in-person support groups, and other greatresources. For more information about these programs or tocontact your chapter, pleasel Call:l Visit:(800) Trials (Research Studies). New treatments forpatients are ongoing. Patients can learn about clinical trialsand how to access them. For more information, pleasecall (800) 955-4572 to speak with our LLS InformationSpecialist who can help conduct clinical-trial searches.When appropriate, personalized clinical-trial navigation bytrained nurses is also available.Advocacy. The LLS Office of Public Policy (OPP)engages volunteers in advocating for policies and laws thatencourage the development of new treatments and improveaccess to quality medical care. For more information, pleasel Call:l Visit:(800) Cancerwww.mycancer.comMy cancer is an educational resource for cancer patients andtheir caregivers. The site is sponsored by the biotechnologycompany Caris Life Sciences and is designed to provideinformation about molecular profiling, cancer biomarkersand the transformation of cancer treatment throughongoing research.PubMedwww.pubmed.govPubMed is a service of the National Library of Medicinethat enables searches for science-based information. Itincludes more than 21 million citations for biomedicalliterature from MEDLINE, life science journals, andonline books.ReferencesFebbo PG, Ladanyi M, Aldape KD, et al. NCCN Task Forcereport: evaluating the clinical utility of tumor markers inoncology. Journal of the National Comprehensive Cancer Network.2011;9(suppl 5):S1-S32.Goetsch CM. Genetic tumor profiling and genetically targetedcancer therapy. Seminars in Oncology Nursing. ollingsworth SJ. Precision medicine in oncology drugdevelopment: a pharma perspective. Drug Discovery Today.2015;20(12):1455-1463.Le Tourneau C, Kamal M, Tsimberidou AM, et al. Treatmentalgorithms based on tumor molecular profiling: the essence ofprecision medicine trials. Journal of the National Cancer Institute.2016;108(4):djv362. doi:10.1093/jnci/djv362.Mayo Clinic Center for Individualized Medicine. -clinic.asp. Accessed December18, 2017.Molecular profiling [search]. My Cancer Web site. Caris LifeSciences, 2017. Accessed April 5, 2017.Molecular profiling [search]. National Cancer Institute at theNational Institutes of Health (NIH). AccessedDecember 18, 2017.Piris MA. The use of molecular profiling for diagnosis andresearch in non-Hodgkin’s lymphoma. Hematology Reports. 2011;3(s3):e2. doi: 10.4081/hr.2011.s3.e2.Stricker T, Catenacci DV, Seiwert TY. Molecular profiling ofcancer—the future of personalized cancer medicine: a primer oncancer biology and the tools necessary to bring molecular testingto the clinic. Seminars in Oncology. 2011;38(2):173-185.This publication is designed to provide accurate and authoritative informationin regard to the subject matter covered. It is distributed as a public service byThe Leukemia & Lymphoma Society (LLS), with the understanding that LLS isnot engaged in rendering medical or other professional services.FS31 Cancer Molecular Profiling I page 6

l Diagnostic markers— A large group of molecular tests can provide information that helps in the diagnosis or classification of a particular disease. An example of a diagnostic marker is the presence of the "Philadelphia chromosome" in chronic myeloid leukemia. l Prognostic markers— These biomarkers help the

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