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  • There is no national cancer registry, so incidence is from NCI’s SEER database which tabulates cancer incidence and death figures from 17 sites (26% population) and from population data from U.S. Census Bureau
  • There is no national cancer registry, so incidence is from NCI’s SEER database which tabulates cancer incidence and death figures from 17 sites (26% population) and from population data from U.S. Census Bureau
  • Lifetime risk: prob that a person will develop or die from cancerRelative risk: compares risk of cancer with exposure/trait to risk of cancer without characteristic
  • Lung ProstateBreastColonLung ColonBreastPancreas
  • -This chart is for ages 40 years and older-Overall, cancer incidence has been declining by 2% each year since 1992-2nd leading cause of death behind heart disease, but in patients over 85 years old – number 1 cause of death is CANCER-in those younger than 40 – leukemia is #1 cause of cancer death.
  • -This chart is for ages 40 years and older-Note that the overall incidence is highest in lung/bronchus, accounting for 29% (15% in men and 14% in women) but specifically for men it is prostate and women breast.-Overall, cancer incidence has been declining by 2% each year since 1992-2nd leading cause of death behind heart disease, but in patients over 85 years old – number 1 cause of death is CANCER-in those younger than 40 – leukemia is #1 cause of cancer death.
  • -This chart is for ages 40 years and older-Note that the overall incidence is highest in lung/bronchus, accounting for 29% (15% in men and 14% in women) but specifically for men it is prostate and women breast.-Overall, cancer incidence has been declining by 2% each year since 1992-2nd leading cause of death behind heart disease, but in patients over 85 years old – number 1 cause of death is CANCER-in those younger than 40 – leukemia is #1 cause of cancer death.
  • Incidence for all sites is highest in africanamerican males
  • In 2002,11 million new cancer cases and 7 million cancer deaths world widenow up to 12 million-45% in asia, 26% europe, 14.5% NA, 7% central/south ameria, 6% africa, 1% australia/New Zealand-Lung cancer is most common cancer in world, breast is second -Cancer death in the world: 1)lung, 2)stomach, 3)liver, 4)colon 5)breast
  • Neoplasia: abnormal proliferation of cells This may be benign, pre-malignant or malignant.Hyperplasia: excessive rate of cell division, but normal architecture & functionMetaplasia: replacement of one differentiated cell type by anotherDysplasia: loss of normal cell maturation, structure & functionAnaplasia: de-differentiation
  • You need only ONE copy of a mutated oncogene for the phenotype
  • Microsatellite instability = long stretches of short nucleotide repeats. They are prone to errors in replications, and may result in frame shifts or changes in promotor regions
  • Red = upregulationGreen = downregulationBlack = constituent expression

Transcript

  • 1. The following material is intended for MSKCC internal medicine housestaff teachingpurposes only. The slides were updated for the LibGuide in 2012-2013.
  • 2. Cancer Epidemiology
  • 3. Overall U.S. Cancer Stats The U.S. population: SEER database (Surveillance, Epidemiology and EndResults): National Cancer Institute database tabulating cancerincidence and mortality figures from 17 sites around thecountry
  • 4. Overall U.S. Cancer Stats Based on SEER database (Surveillance,Epidemiology and End Results) How many NEW cancer cases in the U.S. expectedfor 2010?*not including CIS except bladder and basal cell and squamous cell skin cancers 1.6 million American Cancer Society, Cancer Facts and Figures, 2012 How many cancer deaths in the U.S. expected for2010? 577,190 (about 1,500/day; 1 in 4 deaths) American Cancer Society,Cancer Facts and Figures, 2012
  • 5. Who is at “risk”? Everyone Most significant risk factor: AGE 78% all cancers > 55 years Lifetime risk Men: ~ 1 in 2 (45% risk) Women: ~ 1 in 3 (37% risk) Relative Risk (RR) lung CA in male smokers – RR is 23 Breast CA in women w 1st degree relative – RR is 2 What is the Cost? NIH estimates: Total $ 263.8 billion in 2010
  • 6. Cancer Epidemiology Name the four most common cancers in theoverall U.S. population 1. PROSTATE 2. BREAST 3. LUNG 4. COLON Name the four leading cancers with thehighest mortality in the overall U.S. population 1. LUNG 2. COLON 3. BREAST 4. PANCREAS
  • 7. 2012: Cancer Incidence &MortalityAmerican Cancer Society, Cancer Facts & Figures 2012
  • 8. American Cancer Society, Cancer Facts & Figures 2012
  • 9. American Cancer Society, Cancer Facts & Figures 2012
  • 10. American Cancer Society, Cancer Facts & Figures 2012
  • 11. Cancer Death Rates byRace/Ethnicity (2003-2008)American Cancer Society, Cancer Facts & Figures 2012
  • 12. Cancer Deaths Avoided in Menand Women from 1991-2008American Cancer Society, Cancer Facts & Figures 2012
  • 13. Global Cancer StatsSource: Globocan 2008, IARC 7.6 million deaths in 2008 What Types of Cancer Cause the GreatestNumber of Deaths Worldwide?1. Lung cancer: 1.4 million deaths2. Gastric cancer: 740,000 deaths3. Liver cancer: 700,000 deaths4. Colorectal cancer: 610,000 deaths5. Breast cancer: 460,000 deaths
  • 14. Tumorigenesis &Classification of Cancers
  • 15. Normal Progression ofNeoplasia
  • 16. What makes a tumormalignant?Hanahan & Weinberg. Cell, Vol. 100, 57–70, January 7, 2000Multiple cumulative mutational events are required forthe progression from normal to malignant phenotype.At each successive step, mutated cells gain a growthadvantage.
  • 17. Hanahan & Weinberg. Cell, Vol. 144, 646-74, March 4, 2011
  • 18. Loss of Normal GrowthInhibition
  • 19. Definitions Oncogene: a gene which, upon beingactivated through gain-of-functionmutation or over-expression, promotesreplication or tissue invasion Growth factors Transcription factors Receptor tyrosine kinases Proteins involved in cell cycle
  • 20. Definitions Tumor SuppressorGene: a gene which, upon beinginactivated through loss-of-function mutation orunder-expression, leads tocell growth Proteins which restrict cellgrowth Proteins which promoteapoptosis
  • 21. Genetic mutations andchromosomal abnormalities Point mutations Insertions / deletions Microsatellite instability Epigenetic changes (e.g. methylation) Telomere lengthening Loss of DNA repair genes accelerate theabove changes
  • 22. Tumor Classifications Essentially, any cell type in the body canbecome cancerous. Depending on lineage, a malignant cellwill have certain morphology, stainingcharacteristics onimmunohistochemistry, and will beclassified accordingly.
  • 23. Cellular Origins of TumorsNeoplasmEpitheliumColumnarSquamousGerm CellConnectiveTissue, Bone,MuscleHematopoieticTissueMelanocytesNeuroendocrineCellsCARCINOMA SARCOMALEUKEMIALYMPHOMAMELANOMANEUROENDOCRINEADENOCARCINOMASQUAMOUS CELL CARCINOMAGERM CELL TUMORS
  • 24. Tissue and cellular analysis:Immunohistochemistry oftumorsCarcinoma Sarcoma Leukemia &LymphomaMelanoma NeuroendocrineKeratins + - - - -Vimentin &Desmin - + - - -CD 45, CD19/20,CD 3/4/5/8 - - + - -S-100 - + - + -HMB-45 - - - + -Chromogranin,Synaptophysin,Silver stains- - - - +Stains that are specific for certain carcinomas: PSA, thyroglobulin
  • 25. Concepts in Diagnosis
  • 26. Getting a biopsy sampleTypes FNA Often insufficient;○ No tissue architecture○ Limited sample size Core biopsy Incisional/Excisional biopsy Choose your site wisely Sampling the lymph node or presumed metastatic site cangive both diagnosis and staging information at the sametime Safety, accessibility are always key concerns
  • 27. How we analyze the biopsy Tissue level: architecture; invasion Cellular level: histology / morphology Immunohistochemistry○ Expression ofproteins, receptors,etc. surface (CD) markers(flow cytometry) Chromosomal level: Karyotyping Translocations (FISH) Genetic level: PCR
  • 28. Karyotyping Performed during metaphase, when chromosomes are easilyseen Used often in lymphomas and leukemiaswww.pathology.washington.edu
  • 29. Fluorescence in situHybridization (FISH)http://en.wikipedia.org/wiki/Fluorescence_in_situ_hybridizationhttp://www.kreatech.com
  • 30. Immunohistochemistry Lymphoma: BCL2, Ki-67 Breast: Her2, hormone receptor testinghttp://en.wikipedia.org/wiki/Immunohistochemistryhttp://www.springerimages.com
  • 31. Flow CytometryHow Flow Cytometry Works Lymphomas areclassified by celldifferentiationmarkers (CD)○ CD 2, 3, 4, 7, 8:T-Cells○ CD 19/20: B-cells○ CD 34: StemCells
  • 32. Polymerase Chain Reaction(PCR) Analyze for specific mutations May have prognostic implications○ AML: FLT3, NMP1 May identify therapeutic targets○ NSCLC: EGFR
  • 33. Microarray Used for Oncotype Dx Level of fluorescence denotes level ofexpression compared to control sample http://www.eye-research.orgAdapted from Universitäts-Augenklinik Mainz, Experimentelle Ophthalmologie, Leitung: PD Dr. Dr. F. Grus
  • 34. Concepts in Staging
  • 35. Concepts in Staging: Solidtumors Solid tumors primarily use a TNM system T = Tumor size and invasion into nearby structures N = Lymph node involvement M = Presence of metastasis There are variations on this system Some use tumor markers (serum markers) as part ofstaging○ Testicular cancer○ Melanoma
  • 36. Concepts in Staging cT1N2M0 pT1N2M0 yT1N0M0c: stage given by clinicalexamination of a patient.p: stage given by pathologicexamination of a surgicalspecimen.y: stage assessed afterneoadjuvant therapy.
  • 37. Prognosticating Cancers Staging (T,N,M) Prognostic Tools IPI for diffuse large B-cell lymphoma Adjuvant! Online for breast cancer Performance Status
  • 38. Prognosticating Cancers
  • 39. Prognostic or Predictive Prognostic Biomarkers: Predictive Biomarkers:Stratifies patients based on risk of an outcome(recurrence, overall survival) independent oftreatment• e.g. abnormal LDH in lymphomaStratifies patients based on response to specifictreatment regimen• e.g. Hormone receptor profiling in Breast Cancer
  • 40. Ann Arbor Staging System forHodgkins Disease and Non-Hodgkins LymphomaStage I Stage II Stage III Stage IV• A: Absences of symptoms• B: B symptoms• E: Extranodal extensionAdapted from Skarin. Dana-Farber CancerInstitute Atlas of Diagnostic Oncology. 1991;with permission.
  • 41. IPI and DLBCLSehn L H et al. Blood 2007;109:1857-1861For diffuse large B cell lymphoma treatedwith CHOP:0, 1 factor = low risk: 35% of cases; 5-year survival, 73%2 factors = low-intermediate risk: 27% of cases; 5-year survival, 51%3 factors = high-intermediate risk: 22% of cases; 5-year survival, 43%4, 5 factors = high risk: 16% of cases; 5-year survival, 26%For diffuse large B cell lymphoma treatedwith R-CHOP:0 factor = very good: 10% of cases; 5-year survival, 94%1, 2 factors = good: 45% of cases; 5-year survival, 79%3, 4, 5 factors = poor: 45% of cases; 5-year survival, 55%•Age >60•Elevated LDH•ECOG ≥2•Ann Arbor stage IIIor IV• >1 site ofextranodalinvolvement
  • 42. Concepts in Treatment
  • 43. Types of Treatment Surgery e.g. Lumpectomy Radiation (brachytherapy vs. XRT) Chemotherapy Adriamycin, Cytoxan, Taxol Molecularly Targeted Therapies Trastuzumab (herceptin) Hormonal Therapy Immunologic Therapy Interferon, ipilimumabLocal TherapySystemic Therapy
  • 44. Adjuvant vs. Neoadjuvant Adjuvant Therapy: Additional cancer treatment given after theprimary treatment to lower the risk that thecancer will come back.○ Goal is often to treat micrometastatic diseasefor curative intent Neoadjuvant therapy: Treatment given as a first step to shrink atumor before the main treatment, which isusually surgery, is given.
  • 45. Salvage and Palliative Therapy Salvage: Treatment that is given after the cancer hasnot responded to other treatments. Palliative: Treatment given to relieve the symptomsand reduce the suffering caused by cancerand other life-threatening diseases.
  • 46. Targeted TherapyCataldo VD et al. N Engl J Med 2011;364:947-955.
  • 47. Human Epidermal ReceptorHudis C. NEJM, 2007; 357:39-51
  • 48. RAS/RAF/MEK/ERKHudis C. NEJM, 2007; 357:39-51Cichowski, Nature 2010
  • 49. PI3K/AKTHudis C. NEJM, 2007; 357:39-51
  • 50. VEGFHudis C. NEJM, 2007; 357:39-51Croce C. NEJM, 2008; 358:502-511
  • 51. Concepts in DeterminingResponses
  • 52. RECIST- Response EvaluationCriteria in Solid Tumors Complete Response (CR) No radiographic and no pathologic evidence of disease Partial Response (PR) 30% decrease in sums of longest diameters of lesions(unidimensional) Progression of Disease (POD) 20% increase in sum of diameters of target lesions and anabsolute increase of at least 5 mm.○ Note: the appearance of one or more new lesions is alsoconsidered progression Stable Disease (SD) any tumor shrinkage or growth that does NOT meet above criteria Note: Hematologic Malignancies have own scales
  • 53. Understanding ClinicalResearch: Survival Outcomes Progression-free survival (PFS): length oftime during and after treatment in which apatient with cancer does not get worse Disease-free survival (DFS): length of timeduring and after treatment in which apatient survives without evidence ofdisease Overall survival (OS)
  • 54. Dr. Bosl’s Four Principles ofOncology1. It’s not cancer until proven to be cancer.2. It’s curable until proven otherwise.3. It’s treatable until proven otherwise.4. Even if the cancer isn’t treatable, the patientis always treatable.