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Grand Rounds May 27, 2011 Gene Expression Profiling in Cancer of Unknown Primary Paul Mehan MD

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Grand Rounds May 27, 2011 Gene Expression Profiling in Cancer of Unknown Primary Paul Mehan MD

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    1. Grand Rounds May 27, 2011 Gene Expression Profiling in Cancer of Unknown Primary Paul Mehan MD

    2. Disclosures I have nothing to disclose

    3. Objectives Review the epidemiology, prognosis, and workup of Cancer of Unknown Primary (CUP) Discuss Treatment options for CUP Introduce Gene Expression Profiling and discuss its role in CUP Review a pertinent case

    4. Background Cancer of Unknown Primary Histologically proven malignancies Generally poor prognosis ~40,000 cases annually In majority of patients the primary is not identified with serial evaluations or even on autopsy

    5. Pathology Subtypes Well/Moderately Differentiated Adenocarcinoma (60%) Poorly Differentiated Adenocarcinoma (30%) Squamous Cell Carcinoma (5%) Poorly Differentiated Malignant Neoplasm (5%)

    6. Prognosis Favorable prognosis Poorly Differentiated Carcinoma with Midline Distribution Papillary Adenocarcinoma of Peritoneal Cavity (women) Adenocarcinoma of Axillary Lymph Nodes (women) SCC of cervical lymph nodes Isolated Inguinal Adenopathy Adenocarcinoma with Blastic bone mets (men) Poorly Differentiated Neuroendocrine Carcinoma Small Solitary Tumors

    7. Prognosis Unfavorable Prognosis Male Gender Liver, Lung, or bone mets Nonpapillary Malignant Ascites Multiple Cerebral Metastases

    8. Immunohistochemistry

    9. PET Imaging Sve et al Review of 10 studies evaluating the role of PET in the detection of unknown primary tumors FDG PET detected primary tumors that were not apparent after conventional workup in 41% of patients significantly changed clinical management in 34.7% Detected previously unknown mets in 37% of patients Kolesnikov-Gauthier et al Prospective study using PET to detect primary tumor site in patients with unknown primary (24 patients) Primary tumor confirmed (with f/u or surgery) in six patients (25%). Primary tumor suggested but not confirmed in 5 patients.

    10. Treatment Options Adenocarcinoma Carbo/Taxol +/- Etoposide Gem/Cis Gem/Docetaxel Squamous Cell Cis/Taxane/5-FU Neuroendocrine Small Cell Therapy Carcinoid Therapy

    11. Gene Expression Profiling Genetic Profiling may represent a useful method to complement clinical, morphological, and IHC data Gene Expression Tests Microarrays Thousands of target genes can be measured RT-PCR Smaller subsets of gene markers

    12. Gene Expression Profiling Several Companies have created tests Vary based upon: Technology (RT PCR vs Microarray) Number of Genes Tested Number of Tumor Types Included Ability to perform on FFPE vs FF samples FDA approval

    13. Gene Expression Profiling Pathwork Tissue of OriginTest RNA is extracted from a sample of tumor tissue Target prepared from RNA is labeled with a fluorescent marker Labeled target is spread over the surface of the chip Target binds to complementary gene-specific probes Relative fluorescence intensity of each gene-specific probe is then measured Measures the expression pattern of >2,000 genes Compares it to expression patterns of a panel of 15 known tissue types

    14. Gene Expression Profiling

    15.

    16. Gene Expression Profiling Validation Study 595 FFPE metastatic lesions or poorly/undifferentiated primary tumors (with reference diagnosis) were studied 563 (~95%) yielded 30ng RNA and were processed 549/563 (~98%) were processed successfully 462/549 (~84%) passed prespecified microarray quality control criteria and were used in analysis Agreement with Reference Diagnosis Positive percent agreement was 88.5% Negative percent agreement was 99.1%

    17. Gene Expression Profiling Validation Study Similarity Scores Range 0?100 A measure of the similarity of the RNA expression pattern of the specimen to the RNA expression pattern of the indicated tissue (15 tissues total) Similarity score <5 was 99.8% accurate in ruling out tissue of origin (on average 12/15 tumors SS <5)

    18.

    19. Gene Expression Profiling Varadhachary et al. Purpose Evaluate feasibility of 10 gene RT-PCR to identify the tissue of origin in patients with CUP Methods 120 pts with CUP with FFPE specimens Results Assay successful in 87% 61% assigned tissue of origin Majority of clinical scenerios consistent with reported TOO Patients with colon cancer profiles had better response to colon cancer specific therapies than standard CUP regimens

    20. Gene Expression Profiling Horlings et al Purpose Evaluate gene expression profiling for routine clinical practice in patients with adenocarcinoma of unknown primary Patients and Methods 84 patients with known primary, 38 patients with ACUP 16/38 ACUP classified with extensive IHC FFPE samples analyzed with 1900 feature CupPrint microarray Results 83% of tumors of known origin classified correctly 15/16 ACUP samples confirmed IHC 14/22 ACUP (unconfirmed by IHC) made a valuable contribution to site of origin

    21. Gene Expression Profiling Greco et al Background Accurate identification of CUP patients with colorectal tissue of origin and subsequent treatment with CRC regimens would be expected to improve outcomes over treatment of similar patients with empiric CUP regimens Methods 213 CUP tumor specimens were tested with mRNA-based RT-PCR molecular assays (Veridex Assay or bioTheranostics CancerTYPE ID assay) Results 32 specimens had CRC genetic signatures 29 were treated with first or second line CRC regimens with objective response rates of 69% and 54%, respectively The median, 2 year, and 4 year survival were 22months, 43%, and 38% respectively. Conclusions When treated with site-specific therapy, the CUP patients with CRC genetic signatures had similar median survival to patients with known advanced CRC and superior survival to CUP patients receiving empiric therapy.

    22. Gene Expression Profiling

    23. Clinical Case 53yo male who p/w neck lymphadenopathy and hip pain. PET CT with diffuse LAD involving cervical, supraclavicular, mediastinal, retroperitoneal, and internal/external iliac chains PET CT also noted FDG Avid gastric wall thickening Abdominal MR obtained with no new findings EGD with gastric biopsies unrevealing L Supraclavicular lymph node chosen for biopsy

    24. Clinical Case

    25. Clinical Case

    26. Clinical Case

    27. Clinical Case

    28. Clinical Case

    29. Clinical Case

    30. Clinical Case

    31. Clinical Case Afinitor was started for presumed papillary kidney carcinoma. On first f/u visit he noted marked improvement in cervical lymphadenopathy and improving functional status.

    32. Conclusion Questions???

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