Advances in the Diagnosis and - PowerPoint Presentation

1. Advances in the Diagnosis andTreatment of MalignanciesSteven E Zimmerman MD, FLMI, CLU

2. ObjectiveTraditional methods of diagnosing and treating cancer have been accepted for years, and have been associated with improvements in early detection and successful outcomes. However, as we enter a new era of medical knowledge, these newer, more focused techniques are reaching exciting new heights. This presentation will explore some of these new approaches including improved diagnostic techniques, and targeted and individualized therapies.

3. Source: Kristensen, Nature Rev. Cancer, 14:299, 2014. Systems Biology of Cancer

4. Types of TreatmentsSurgeryRadiation TherapyChemotherapyHormone TherapyImmunotherapyTargeted TherapyPrecision Medicine

5. Surgery

6. Radiation TherapyA local modality in the treatment of cancerUses high-energy particles or waves, such as x-rays, gamma rays, electron beams, or protons, to destroy or damage cancer cellsSuccess depends upon the difference in sensitivity between the tumor and normal tissueMethods of deliveryExternal beam - directs high-energy rays from outside the body into the tumorInternal (brachytherapy) - radiation source sealed in a small that is placed very close to or inside the tumor, so that it harms as few normal cells as possibleSystemic - radioactive drugs given by mouth or put into a vein then travel throughout the body

7. ChemotherapyDrugs used for cancer treatmentGoals of chemotherapy treatmentCureControlPalliationChemotherapy works with the cell cycle – at different phases of the process of forming new cellsCancer cells tend to form new cells more quickly than normal cells and this makes them a better target for chemotherapy drugs

8. Types of Chemotherapy DrugsAlkylating agents – damage DNACarboplatin, Cisplatin, Cytoxan, MephalanAntimetabolites – interfere with DNA and RNA growth by substituting for the normal building blocks of RNA and DNA5-FU, 6-MP, Hydroxyurea, MethotrexateAnti-tumor antibiotics – work by changing the DNA inside cancer cells to keep them from growing and multiplyingDaunorubicin, Adriamycin, Bleomycin, Mitomycin-CTopoisomerase inhibitors – interfere with enzymes called topoisomerases, which help separate the strands of DNA so they can be copiedTopotecan, Etoposide, Teniposide

9. Types of Chemotherapy DrugsMitotic inhibitors – work by stopping cells from dividing to form new cells but can damage cells in all phases by keeping enzymes from making proteins needed for cell reproductionEstramustine, Paclitaxel, Vinblastine, VincristineCorticosteroidsPrednisone, Methylprednisolone, Dexamethasone Other chemotherapy drugs L-asparaginase

10. 2015Chemotherapy Advances20042004-2005Advances in both common and rare cancersSmarter, more refined approaches Increasing and decreasing treatment aggressiveness to maximize benefit Adjuvant CT for lung, pancreatic cancersBiomarker tests identify patients for adjuvant CTChemo dosing halved for low-risk neuroblastoma1998AVBD replaces MOPP for pediatric Hodgkin lymphoma2007Long-term mortality halved for pediatric cancer survivors

11. Hormone TherapySex hormones, or hormone-like drugs, that are used to slow the growth of breast, prostate, and endometrial (uterine) cancers, which normally grow in response to natural sex hormones in the bodyWork by making the cancer cells unable to use the hormone they need to grow, or by preventing the body from making the hormone

12. Immune TherapyA biological therapy – type of treatment that uses substances made from living organisms to treat cancer and other diseasesTypes of immune therapyMonoclonal antibodiesCytokinesTreatment VaccinesBCGAdoptive cell transfer

13. Monoclonal AntibodiesAntibodies that are made by identical immune cells that are all clones of a unique parent cell

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15. Types of Monoclonal AntibodiesNaked monoclonal antibodiesConjugated monoclonal antibodiesBispecific monoclonal antibodies

16. Naked Monoclonal AntibodiesAntibodies that work by themselvesNo drug or radioactive material attached to themMechanisms of actionboost a person’s immune response against cancer cells by attaching to them and acting as a marker for the body’s immune system to destroy them – e.g. alemtuzumab (Campath®)boost the immune response by targeting immune system checkpointsattach to and block antigens on cancer cells (or other nearby cells) that help cancer cells grow or spread – e.g. trastuzumab (Herceptin®)

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18. Conjugated Monoclonal AntibodiesMonoclonal antibodies (mAbs) joined to a chemotherapy drug or to a radioactive particleUsed as a homing device to take one of these substances directly to the cancer cellsTypes of conjugated mAbsRadiolabeled antibodies – e.g. Ibritumomab tiuxetan (Zevalin®)Chemolabeled antibodies – e.g. Brentuximab vedotin (Adcetris®), Ado-trastuzumab emtansine (Kadcyla®, also called TDM-1)

19. Bispecific Monoclonal AntibodiesMade up of parts of 2 different mAbs, meaning they can attach to 2 different proteins at the same time

20. ADEPT – antibody directed enzyme prodrug therapyADCC – antibody dependent cell-mediated cytotoxicityCDC – complement dependent cytotoxicityMab – monoclonal antibodyscFV – single-chain FV fragmentCarter P: Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 2001;1:118-129

21. Immune Checkpoint Inhibitors Checkpoints – molecules on certain immune cells that need to be activated (or inactivated) to start an immune responseCancer cells sometimes find ways to use these checkpoints to avoid being attacked by the immune system

22. PD-1 or PD-L1 InhibitorsDrugs that target PD-1 or PD-L1PD-1 on T cells binds to PD-L1 on normal cells – turns “off” T cellPD-L1 on tumor cells prevents PD-1 from turning “on” T cellMonoclonal antibodies that target either PD-1 or PD-L1 can block this binding, activating T cellPD-1 inhibitors – e.g. Pembrolizumab (Keytruda), Nivolumab (Opdivo)PD-L1 inhibitors – e.g. Atezolizumab (Tecentriq)

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24. Anti CTLA-4 InhibitorCTLA-4 is another protein on some T cells that acts as a type of “off switch”Anti CTLA-4 inhibitor attaches to CTLA-4 and stops it from working – e.g. Ipilimumab (Yervoy)

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26. Rise of Immunotherapy20142011Long-term disease control against recalcitrant cancersGame-changing discoveries – more comingIpilimumab introduced for melanomaPembrolizumab, nivolumab approved for melanoma2015-2016PD-1/L-1 drugs benefit even more of cancers

27. CytokinesCategory of small proteins released by cells that has a specific effect on the interactions between cells, on communications between cells or on the behavior of cells Cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factorsInterferon alpha – used to treat renal cell carcinoma, melanoma, multiple myeloma, some types of leukemiaInterleukin 2 – used to treat renal cell cancer

28. Cancer VaccinesTwo main typesVaccines to prevent cancerVaccines to treat cancerHPV vaccine is the only preventative vaccine availableProtects against infection with the human papilloma virusMarkedly reduces risk of cancer of the cervix if vaccination occurs before exposure to the HPVSipuleucel-T (Provenge®) only vaccine approved in US to treat cancerUsed to treat advanced prostate cancer

29. Sipuleucel-T Mechanism of Action

30. Adaptive Cell Transfer

31. Targeted Therapy

32. Targeted Therapy The foundation of precision medicineType of cancer treatment that targets the changes in cancer cells that help them grow, divide, and spreadTypes of targeted therapySmall-molecule drugs – small enough to enter cells easily, so they are used for targets that are inside cellsMonoclonal antibodies – attach to specific targets on the outer surface of cancer cells

33. How Targeted Therapy Works Against CancerHelp the immune system destroy cancer cellsStop cancer cells from growingStop signals that help form blood vesselsDeliver cell-killing substances to cancer cellsCause cancer cell deathStarve cancer of the hormones it needs to grow

34. Precision MedicineAn approach to patient care that allows doctors to select treatments that are most likely to help patients based on a genetic understanding of their diseaseAlso called personalized medicineNot likely to replace traditional cancer treatmentsTumor must have a genetic change that can be targeted by a drug that is approved or being tested

35. Precision MedicineCancers classified by molecular abnormalities and site of originExceptional success when treatment is matched to a driver mutation 20011998First targeted drug: rituximabTrastuzumab introduced for HER2+ breast cancerImatinib introduced1997-2016100+ FDA-approved targeted cancer drug indications1997Image Sources: Slamon D, et al.  Engl J Med 2001; 344:783-792; NCI; FDA

36. Molecular Diagnostics of TumorsTraditional pathology reports includeTumor typeWHO-codepTNM statusDignity – i.e. benign, malignant, in situ carcinoma, or borderlineHistogenesis and prognostic predictive relevance is limitedUse of molecular data can be very relevant for selecting optimal treatment

37. Breast CancerClassical morphology-based classification had been replaced by the molecular classificationFive different subtypes determined by gene expression analysis as well as immunohistochemistryluminal-Aluminal-B/HER2-negativeluminal-B/HER 2-positiveHER2-positive/non-luminaltriple negative

38. Breast CancerIn clinical practice, standard approach uses only immunohistochemical analysis to determine estrogen receptor, progesterone receptor and HER2In past several years, newer diagnostic assays using mRNA analysis of gene expression have identified low risk tumors that might not need chemotherapy – luminal-A tumorsOncotypeDX assayEndopredict assayPAMSO/Prosigna test

39. Overview of Molecular Tests with Therapeutic ImplicationsTumor typeAffected gene(s)Type of alterationMethod for detectionRelated treatmentBreast cancerHER2AmplificationIHC, ISHHerceptin PIKCASNVSequencingReduced response to anti-HER2 treatment, in particular double blockade (Trastuzumab / Lapatinib) Gene expression assays (EndoPre-dict, OncotypeDX etc.)mRNA levelsqRT-PCRPrognostic assay (endocrine Tx vs Chemoendocrine Tx)Colorectal cancerRAS (KRAS, NRAS)SNVSequencingCetuximab / PanitumumabGISTKITSNV, indelSequencingImatinib, Sunitinib PDGFRSNVSequencingImatinib, SunitinibMalignant melanomaBRAFSNVSequencingVemurafenib, Dabrafenib, Trametinib KITSNV, indelSequencingSunitinib, Dasatinib, Imatinib

40. Overview of Molecular Tests with Therapeutic ImplicationsTumor typeAffected gene(s)Type of alterationMethod for detectionRelated treatmentNSCLCEGFRSNV, MNV, indelSequencingGefitinib, Erlotinib, Afatinib, Dacomitinib ALKTranslocationISH, IHC, SequencingCrizotinib, Ceritinib, Alectinib ROS1TranslocationISH, SequencingCrizotinib METAmplificationISH, SequencingResistance to EGFR TKIsClassical hairy cell leukemiaBRAFV600E mutationSequencingVemurafenibBurkitt lymphoma, DLBCL, transformed FLMYCTranslocation, amplification, overexpressionIHC for MYC protein, FISHBET inhibitors, Protein translation inhibitorsDLBCL, FL, MCL, SLL/CLLBCL2Translocation, amplification, overexpressionIHC for BCL2 protein, FISHBH3 mimetics

41. Abbreviations: ABC – activated B-cellDLBCL – diffuse large B-cell lymphoma FL – follicular lymphomaGCB – germinal center B-cellIHC – ImmunohistochemistryIndel – insertion or deletion ISH – In situ hybridization MCL – mantle cell lymphoma MNV – multiple nucleotide variation PCR – Polymerase chain reaction SLL/CLL – small lymphocytic lymphoma/chronic lymphocytic leukemia SNV – single nucleotide variationTKI – Tyrosine Kinase Inhibitor

42. SummaryCancer is not one disease, so a “cure” is not a reasonable conceptAdvances in all forms of diagnosis and therapy over the past 50 years has led to a significant improvement in survival of cancer patientsNewer forms of therapy including immunotherapy and targeted therapy have grown from the human genome project and will be a significant part of cancer therapyPrecision therapy, an individualized approach to cancer treatment, holds great promise and is likely to be a mainstay of treatment in the near future

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