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Molecular diagnosis of UPT: when?

UPT 3-5% of all tumors at presentation. 15% remain undiagnosed (estimated to be 4000 per year in the USA). Of which about 85% diagnosed by clinical history, physical examination, conventional lab tests, radiologic imaging, morphology, routine immunohistochemistry). Molecular diagnosis

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Molecular diagnosis of UPT: when?

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  1. UPT 3-5% of all tumors at presentation 15% remain undiagnosed (estimated to be 4000 per year in the USA) Of which about 85% diagnosed by clinical history, physical examination, conventional lab tests, radiologic imaging, morphology, routine immunohistochemistry) Molecular diagnosis of UPT: when? ad hoc molecular tests

  2. Molecular diagnosis of UPT: methods Serum markers Immunohistochemistry (low-medium throughput) Multiplex RT-PCR (medium-throughput) Genomic arrays (high throughput) (a) cDNA arrays (b) oligo arrays (c) array CGH 5. Proteomics (a) capillary electrophoresis (b) mass spec

  3. Molecular profiling of UPT (or CUP) from 15 published original papers

  4. Molecular classification of UPT/CUP: open strategical issues HUGE training datasets are mandatory (n > 500) ‘Difficult’ specimens (e. g. necrosis) Bioinformatics approaches crucial (molecular taxonomy - deconvolution)

  5. Crucial features of molecular CUP classifications Frozen vs FFPE Arrays vs PCR mRNA vs miRNA Size of the selected geneset Size of training and validation datasets CUP numbers Number of molecular classes identified Additional aspects • Algorithms • Commercial development

  6. CUP in the literature

  7. Molecular diagnosis of CUPs: a literature selection (1 of 3)

  8. Molecular diagnosis of CUPs: a literature selection (2 of 3)

  9. Molecular diagnosis of CUPs: a literature selection (3 of 3)

  10. 4. Large signatures and the spectrum of data overfitting (small is beautiful) Molecular classification of CUP: considerations Genesets non-overlapping among different groups FFPE and multiplex RT-PCR are taking over 3. microRNAs vs RNAs: miRNAs easier to isolate from FFPE and high in hierarchy, but CG-rich, highly homologous to each other (Locked nucleic acids? LNA Exiqon) … 5. The bioinformatics/biotechnology war 6. The commercial war (and its weapons: FDA, the web, publications, conflicts of interest etc.) Fitting too closely with the training set when the training set is small

  11. Bioinformatics: a few examples

  12. Hyerarchical clustering Van Laar 2009

  13. Molecular classification of CUP: very technical details A dendrogram (nodes, branches and leaves) generated by the leave-one-out cross validation (LOOCV) algorithm Rosenfeld 2008

  14. Principal Component analysis (PCA)

  15. CUP and the market

  16. Molecular classifiers of CUP on the market Rumors about Veridex (J & J) - the owner of Cell Search

  17. The Pathwork TOO (tissue of origin) from Stanford University and Pathwork Diagnostics: the first FDA approved molecular taxonomy for CUP

  18. A snapshot of the Theros Cancer Type ID report

  19. money … money …money (the magicl world of in vitro diagnostic multivariate index assays - IVDMIA) The Pathwork TOO platform is probably evolving (FFPE-grade + possibly short signature) 2. Cancer TYPE ID is just one of the molecular classifiers of Agendia/Biotheranostics: MammaPrint 70-gene signature e Breast cancer Index two-signature, both FDA-approved … why Cancer TYPE ID not yet approved? 3. Rosetta Genomics advertises miRView as a cutting edge miRNA platform (2 more available)

  20. Molecular classification of CUP: limitations and applications Accuracy mostly evaluated on Cancers of Known Primary (CKP) not REAL Cancers ofUnknownPrimary (CUP) Drop in accuracy in poorly differentiated CUPs IHC and CUPPrint were discordant in 11 out of 24 cases (only1 study available) In approximately half of 21 CUPs, molecular diagnosis was reported to have affected clinical management In colon cancer, 5 out of 6 patients obtained objective clinical response to a change in chemotherapy At autopsy pancreas and lung most frequent but breast and colon most frequent by molecular analysis. Why? Unique molecular features of CUP? Regardless of TOO identification, refractoriness to therapy is the hallmark of CUP. Does this underpin unique molecular features?

  21. met mutation normal pre-malignant proliferant primary Classical and non-classical models of the metastatic cascade Classical (late dissemination) modified from Christoph A. Klein, Science Sept. 2008 Non-classical (early dissemination) UPT

  22. CD8+ CD8 CD8- 200 days Occult tumor models and CUP edited unedited elimination equilibrium escape MCA UPT Koebel Nature Dec 2007

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