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Pathology Role in Targeted Therapy Luis R. Lozada- Muñoz, MD Staff Pathologist Hato Rey Pathology Associates Eras of Pathology • Diagnostic era 1800-1960 • Prognostic era 1960- 1990’s • Therapeutic guidance era - now Dr. Edwin Klebs Biomarkers • Is a specific physical trait or measurable biologically produced change in the body connected with disease or health condition. • A marker of biological status. • Give us critical information to understand the pathogenesis of disease. • Use as diagnostic and prognostic markers Examples of Biomarkers • • • • • Biomarker Hemoccult Duke stage Serum CEA MSI KRAS Assay • • • • • Digital exam Histology Blood test PCR Sequencing What it detects •Occult Blood •Risk stratification •Recurrent disease •Hereditary cases •Therapeutic Response Personalized Medicine • US Congress defines personalized medicine as the application of genomic and molecular data to better target the delivery of health care, facilitate the discovery and clinical testing of new products and help determine a person’s predisposition to disease or condition. Personalized Medicine • • • • • • Also the medicine of the omics Genomics Proteomics Metabolomics Pharmacogenomics Companion assays Current Reactive Medical Care Model • Diagnosis---------Select Therapeutics--------------Select Therapeutics------Select Therapeutics----Select Therapeutics------Select Therapeutics. The Personalized Medicine Paradigm • Predisposition screening------Diagnosis and prognosis-------” Right Drug and dose-----monitoring Personalized Medicine Oncology • • • • Testing for BRCA1/ BRCA2 genes. Minimal residual disease detection Targeted therapy Chemotherapy decision ( Oncotype Dx, Mammaprint) • Therapeutic Drug Monitoring Targeted therapy • Medications that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth. • May be more effective and less harmful. Targeted therapy • Small molecules • Monoclonal antibodies Targeted therapy small molecules (ib) • Imatinib mesylate (Gleevec)- CML, GIST and may be effective for dermatofibrosarcoma protuberns. • Gefinitib (iressa)-non small cell carcinoma. • Erlotinib (tarceva)- non small cell carcinoma • Bortezomib (Velcade) -Multiple myeloma • Sunitib( Sutent ) Renal cell carcinoma and GIST • Lapatinib (Tyrkerb) – breast carcinoma HER2 + • Tamoxifen • BCL 2 antagonist Obatoclax, ABT 263 and Gossypol. Targeted therapy monoclonal antibodies • • • • • Rituximab B cell NHL Trastuzumab (Herceptin) Cetuximab (Erbitux) Bevacizumab (Avastin) Eculizumab ( Soliris) Targeted therapy IHC guided • Tamoxifen and aromatase inhibitors –ER positive • Gleevec (GIST)- CD 117 • Trastuzumab- Her 2 neu* • Antagonist of BCL 2* Targeted therapy FISH guided • Trastuzumab • Gleevec -CML Targeted therapy Flow cytometry guided • Rituximab- CD 20 + NHL • Eculizumab ( Soliris ) PNH Targeted therapy Conventional Cytogenetic guided/PCR • Gleevec CML Targeted therapy gene sequencing guided/PCR • Erbitux (Cetuximab) • KRAS • BRAF Targeted therapy Histologic/IHC guided • • • • • Gefitinib ( Iressa) NSCCa Erlonitib (tarceva) metastatic NSCca Bortezomib ( Velcade ) Multiple Myeloma Sunitib ( Sutent) GIST and Renal cell Ca Bevacizumab ( Avastin ) Adenocarcinomas Targeted Therapy in Melanoma Imatinib mesylate 0-40% mutated C-KIT Cell Membrane Farnesyltransferase inhibitors BRAF Sorafenib CI-1040 PD-0325901 AZD6244 Antrax LT NRAS PTEN PI3K 20% mutated Deletion, epigenetic changes or mutation in 50% 60% mutated MEK ERK AKT CELL SURVIVAL Bcl-2 Amplification or activation in 60% Oblimersen mTor RNAi MITF Amplification In 20% TRANSCRIPTION Rapamycin CCI-779 RAD -001 Metabolism of tamoxifen by CYP450 enzymes Tamoxifen CYP3A4/3A5 CYP2D6 4-OH Tamoxifen N-desmenthyl Tamoxifen CYP3A4/3A5 Endoxifen Anti-estrongenic effect in tumor cell Conclusion • Pathology always has influenced therapy but now our knowledge is expanding and clinical medicine is more dependable of pathology lab tests for therapy selection. Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease."
