Biomarkers in Anatomic Pathology Adding Value in Diagnostics
Biomarkers in Anatomic Pathology Adding Value in Diagnostics Jennifer Hunt, MD, MEd, FCAP
Biomarkers in Anatomic Pathology: Adding Value in Diagnostics Jennifer L. Hunt, M. D. , M. Ed. Section Head, Surgical Pathology Director, Head and Neck and Endocrine Pathology Director, Molecular Anatomic Pathology Unit
Auguste Nélaton (1807 – 1873) “The microscope is not, for the biologist or physician, an instrument which he can indifferently make use of; its employment is absolutely necessary. Accustomed to judge from exterior characters alone, pathologists should not be astonished that many results obtained by them are shown to be inexact or incomplete by the microscope. Far from believing that the fault comes from the new information added by the microscope, it is the history of diseases which must be taken up again and revised, starting from the new and much more precise notions of the tissue furnished by microscopy. ” CAP Foundation Futurescape | 2008 | 5
Zaccharias Janssen (15901608): First Microscope Anton van Leeuwenhoek (16321723): Bacteria 1600 Robert Hooke (1635 -1703) Father of Microscopy 1700 Rudolph Virchow (1821 -1902): Father of Microscopic Pathology 1800 1900 Carl Rokitansky (18041878): Father of Autopsy Pathology
Peyton Rous (1910): Oncogenes (Nobel Prize 1966) Ernst Ruska & Max Knott (1931): Electron Microscope (Nobel Prize, 1986) Kary Mullis (1983): Polymerase Chain Reaction (Nobel Prize, 1993) Frederick Sanger (1975): Sequencing (Nobel Prize, 1980) 1950 1960 Watson & Crick (1953): DNA (Nobel Prize, 1962) 1970 1980 Alfred Knudson (1971): Tumor suppressor genes (Lasker Award, 1998) 1990 2000 Sternberger (1978): Immunocytochemistry
Gross Exam (1500 -1800) Microscopic Analysis (1800 -1930) Electron Microscopy (1930 -1980) IHC (1980 -2000) DNA (2000) Micro
Agenda: Biomarkers in AP • The Past: Diagnosis • The Present: Prognosis • The Future: Therapeutics 1800 Diagnostic Assay Era 1960 Prognostic Assay Era 2000 Therapeutic Assay Era CAP Foundation Futurescape | 2008 | 9
CAP Foundation Futurescape | 2008 | 10
Biomarkers: Definition • “A specific physical trait or measurable biologically produced change in the body connected with a disease or health condition” • Any marker of biological status CAP Foundation Futurescape | 2008 | 11
Biomarkers: Examples Biomarker Hemoccult Dukes Stage Serum CEA Microsatellite instability KRAS Assay Digital exam Histology Blood test PCR What it detects Occult blood Risk stratification Recurrent disease Hereditary cases Sequencing Therapeutic response CAP Foundation Futurescape | 2008 | 12
Drivers of Biomarker Testing • Understanding pathogenesis • Better diagnosis • Better prognostic information • Better understanding of therapeutic response CAP Foundation Futurescape | 2008 | 13
Biomarkers in Pathology • The Past: Diagnosis • The Recent Past: Simple Prognosis • The Present – Advanced Prognosis – Understanding Biology • The Future: Therapeutics CAP Foundation Futurescape | 2008 | 14
Colon Cancer Diagnostics • 1700’s: Gross diagnosis • 1800’s: Microscopic diagnosis CAP Foundation Futurescape | 2008 | 15
1. Abdominal mass with cachexia and bowel symptoms 2. Abdominal mass and histologic identification of tumor 3. Gradual bowel symptoms, cachexia, stricture symptoms, and histologic identification of tumor Einhorn M, 1900 CAP Foundation Futurescape | 2008 | 16
Gross Exam (1500 -1800) Microscopic Analysis (1800 -1930) Electron Microscopy (1930 -1980) IHC (1980 -2000) DNA (2000) Micro CAP Foundation Futurescape | 2008 | 17
Biomarkers in Pathology • The Past: Diagnosis • The Recent Past: Simple Prognosis • The Present – Advanced Prognosis – Understanding Biology • The Future: Therapeutics CAP Foundation Futurescape | 2008 | 18
Colon Cancer Anatomic Prognosis • 1932: Dukes Staging System (rectal) • 1953: Astler-Coller modification of Dukes • 1965: AJCC Staging System CAP Foundation Futurescape | 2008 | 19
Colon Cancer Biology & Prognosis • 1990 -1993: Genetics of familial adenomatous polyposis (FAP) – 1991: APC locus identified – 1993: APC gene cloned • 1993: Genetics of hereditary nonpolyposis colorectal carcinoma (HNPCC) – Microsatellite instability identified CAP Foundation Futurescape | 2008 | 20
Genetic of Colon Cancer Tumor Suppressor Gene (85%) 15% 5% Microsatellite unstable cases (15%) HNPCC CAP Foundation Futurescape | 2008 | 21
Genetics of Colon Cancer Tumor suppressor gene (APC) Microsatellite Negative instability DNA mismatch: hereditary Positive DNA mismatch: sporadic Positive Immunostains BRAF mutation N/A h. MSH 2 (-) h. MLH 1 (-) N/A Wild-type Mutant (40%) h. MLH 1 methylation N/A Negative Positive CAP Foundation Futurescape | 2008 | 22
Gross Exam (1500 -1800) Microscopic Analysis (1800 -1930) Electron Microscopy (1930 -1980) IHC (1980 -2000) DNA (2000) Micro CAP Foundation Futurescape | 2008 | 23
Biomarkers in Pathology • The Past: Diagnosis • The Recent Past: Simple Prognosis • The Present – Advanced Prognosis – Understanding Biology • The Future: Therapeutics CAP Foundation Futurescape | 2008 | 24
Approved Targeted Therapies Drug Target of drug Trade name Tumor Gefitinib Erlotinib Cetuximab Panitumumab EGFR Iressa Tarceva Erbitux Vectibix Lung Colon Trastuzimab Her 2/neu Herceptin Breast Bevacizumab VEGF Avastin Colon Imatinib mesylate Tyrosine kinase Gleevec GIST, CML Bortezomib Proteasome Velcade Multiple myeloma, Mantle cell lymphoma Rituximab CD 20 Rituxan B cell lymphoma CAP Foundation Futurescape | 2008 | 25
Success of Targeted Therapy Response Cost Side Effects CAP Foundation Futurescape | 2008 | 26
Cost Per Month • Gleevec: $3, 000 • Herceptin: $2, 800 • Rituxan: $12, 000 • Iressa: $1, 800 75% of$2, 700 personal bankruptcy is caused by • Tarceva: a catastrophic illness • Erbitux: $9, 600 Himmelstein DU. 24(1), 2005 • Vectibix: $8, 000 CAP Foundation Futurescape | 2008 | 27
Future: Biomarkers for Therapeutics • Selection for therapeutics – Companion diagnostics • Monitoring of therapeutic response – Minimal residual disease testing • Predicting resistance to therapeutics – Markers of tumor resistance CAP Foundation Futurescape | 2008 | 28
Courtesy of Dr. S. Dacic EGFR Extracellular Domain L CEL NE BRA M E M PROLIFERATION Transmembrane Domain TRANSMEMBRANE Cytoplasmic Domain APOPTOSIS ANGIOGENESIS
Epidermal Growth Factor Receptor • Altered in many tumors – Protein Expression – Gene copy number – Gene sequence CAP Foundation Futurescape | 2008 | 30
Epidermal Growth Factor Receptor • Blockade of EGFR pathway – Monoclonal antibody – Small molecule inhibitors of tyrosine kinase CAP Foundation Futurescape | 2008 | 31
Monoclonal Ab (Erbitux) Small molecule inhibitors (Iressa, Tarceva)
Colon Cancer Therapeutics • 2004: EGFR Pathway in colon cancer – Erbitux approved by FDA for colon cancer treatment – EGFR antibody approved by FDA • 2008: Predictors of resistance – KRAS mutations insensitivity to Erbitux CAP Foundation Futurescape | 2008 | 33
Erbitux Timeline June, 2008 December, 2001 February, 2004 FDA Approval • Erbitux • EGFR Pharm. Dx FDA negative report March, 2009 Early 2005 October, 2007 Completion of CA 225006 Literature against EGFR IHC testing ASCO data: KRAS Mutation Anticipated Completion CAP Foundation Futurescape of | 2008 | 34 CA 225014
Challenges for Pathology • Biomarker selection • Testing – Assay development – Validation – Interpretation Pathologist Training • Operational impediments – Patents – Cost and reimbursement CAP Foundation Futurescape | 2008 | 35
Who Validates New Assays? • Laboratory technical staff • Anatomic pathologists • Molecular pathologists CAP Foundation Futurescape | 2008 | 36
Number of people Predicted Labor Shortage by 2020 Estimated Labor Shortage by 2020 Auerbach, D. Health Affairs. 26(1), 2007: 178 AAMC Study on Physician Shortage, August 2007 Castleberry BM, Lab Med 30, 1999: 174 CAP Foundation Futurescape | 2008 | 37
Absolute Number Molecular Genetic Pathology Fellowships Source http: //www. acgme. org/adspublic/ Accessed March 22, 2008 CAP Foundation Futurescape | 2008 | 38
Who Signs Out Results? • Send-out laboratories • Anatomic pathologists • Molecular pathologists CAP Foundation Futurescape | 2008 | 39
AMP Test Directory • Microsatellite instability: 11 laboratories • EGFR: 5 laboratories • K-RAS: 4 laboratories http: //www. amptestdirectory. org/ Accessed 6/2/2008 CAP Foundation Futurescape | 2008 | 40
Training of Pathologists Data courtesy of CAP June, 2008 CAP Foundation Futurescape | 2008 | 41
Hybrid capture for HPV (1995) Quantitative PCR (1992) PCR (1983) IHC (1978) Sequencing (1975)
Absolute Number of MGP Applicants End of Grandfather Period Source: https: //www. abpath. org Accessed 3/23/2008 CAP Foundation Futurescape | 2008 | 43
Challenges for Pathology • Biomarker selection • Testing – Assay development – Validation – Interpretation • Operational impediments – Patents – Cost and reimbursement CAP Foundation Futurescape | 2008 | 44
Gross Analysis Microscopic Analysis Electron Microscopy Immunohistochemistry DNA Micro CAP Foundation Futurescape | 2008 | 45
Auguste Nelaton (1807 – 1873) (Modified for 2008) “Biomarker testing is not, for the biologist or physician, “The microscope an instrument which (s)h he can indifferently make use of; its employment iseabsolutely necessary. the microscopic appearance, Accustomed to judge from exterior characters alone, pathologists should not be astonished that many results obtained by them are shown to be inexact or incomplete by the microscope. biomarkers. Far from believing that the fault comes from the new information added by the biomarkers, microscope, it is the history of diseases which must be taken up again and revised, starting from the new and much more precise notions of the tissue furnished by microscopy. ” biomarkers. ” CAP Foundation Futurescape | 2008 | 46
CAP Foundation Futurescape | 2008 | 47
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