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Research Presentation on Thyroid Cancer

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Research Presentation on Thyroid Cancer PowerPoint Presentation

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Slide 1 - Research Presentation Jason M. Leibowitz, MD June 25, 2009 Preceptor: Marcia S. Brose, MD PhD Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870
Slide 2 - Overview Background Hypothesis Methods Results Discussion Conclusions & Future Directions
Slide 3 - Thyroid Cancer in the United States Thyroid cancer is the most common endocrine neoplasm. Thyroid cancer will be diagnosed in 33,550 individuals (8070 men and 25,480 women) this year. From 1997-2004 incidence of thyroid cancer increased by 6.2% mostly due to increased detection. From 1985 to 2004 mortality rate increased by 0.3% a year.
Slide 4 - RAI-Refractory Disease 25-50% of metastatic thyroid cancers lose ability to take up Iodine. Iodine Uptake inversely correlates with survival. This is attributed to down regulation of the Na+/I- Symporter (NIS). Limited treatment options for unresectable thyroid cancer refractory to RAI.
Slide 5 - Molecular Changes in Thyroid Cancer
Slide 6 - Molecular Pathway involved in Thyroid Cancer Activation of MAPK pathway Oncogenic activation of this pathway in 70% of all thyroid cancers. BRAF is a serine threonine kinase Xing, 2007.
Slide 7 - BRAF V600E in Thyroid Cancer 2003: The BRAF V600E mutation is the most common genetic alteration in thyroid cancer, occurring in about 45% of sporadic papillary thyroid cancers (PTCs). V600E
Slide 8 - BRAF V600E Point mutation in 40-45% of PTC Upregulation of MMP, VEGF --> invasion, angiogenesis Silencing of tumor suppressive genes, genes involved in iodine transport BRAF mutation associated with multiple negative prognostic indicators.
Slide 9 - RAS Family of small G-proteins involved in transduction of cellular signals from the cell membrane. Mutations in RAS gene lead to inappropriate activation with constitutively activated downstream pathways and also promote chromosomal instability. 20% FTC contain a RAS mutation RAS mutations may correlate with aggressive behavior (tumor dedifferentiation and poorer prognosis).
Slide 10 - Targeted Therapy in Thyroid cancer Loss of differentiation (inability to trap RAI), unresectable lesion, leads to poor prognosis BRAF inhibitors BAY 43-9006 (Sorafenib) Multikinase inhibitor
Slide 11 - Sorafenib Orally active multikinase inhibitor (study dose 400mg BID). Monoclonal antibody with multiple targets including BRAF, VEGFR1, VEGFR2. Blocks tumor cell proliferation and angiogenesis. FDA approved for treatment of RCC and hepatocellular carcinoma.
Slide 12 - Targeted Therapy and Genotype K-RAS gene mutation and metastatic colorectal carcinoma. Recent results from Phase II & III clinical trials demonstrate that patients with metastatic colorectal cancer benefit from anti-EGFR therapy. Patients with K-RAS mutation in codon 12 & 13 should not receive anti-EGFR therapy since they do not receive any benefit. EGFR and non-small cell lung cancer: Epithelial growth factor receptor 10% mutated in NSCLC EGFR mutations are predictors of TKIs responsiveness and may show a long lasting response to TKIs EXON 19 Deletion respond better to TKIs.
Slide 13 - Prior Data 84 weeks N= 52 N=43 WDTC
Slide 14 - Papillary vs. Follicular P<0.095 FTC = 19 PTC= 24
Slide 15 - Prior Data Conclusions from prior data: Improved PFS with Sorafenib. Improved PFS of FTC treated with Sorafenib when compared to PTC.
Slide 16 - Overview Background Hypothesis Methods Results Discussion Conclusions & Future Directions
Slide 17 - Hypothesis There are specific genotypes (i.e. BRAF V600E, RAS mutations) that predict favorable response to targeted therapy (Sorafenib).
Slide 18 - Null Hypothesis Specific genetic mutations do not predict response to targeted therapy in thyroid cancer.
Slide 19 - Overview Background Hypothesis Methods Results Discussion Conclusions & Future Directions
Slide 20 - Research Plan Tissue samples collected from patients with treatment-resistant thyroid cancer with long term follow-up (approximately 30 patients). All patients received targeted therapy (Sorafenib). Samples with WDTC analyzed for mutations in BRAF and RAS genes when available: BRAF - V600E RAS - Exon 12, 13, 61
Slide 21 - RESULTS
Slide 22 - Sequence Output Computer program interprets data and produces an electropherogram, (aka trace) Each peak represents a base: A = Adenosine T = Thymine C = Cytosine G = Guanine N = Reading cannot be determined
Slide 23 - Overview Background Hypothesis Methods Results Discussion Conclusions & Future Directions
Slide 24 - Results of Stage 1 Analysis N= 30 M = F = 15 PTC=17, FTC= 9, Other (ATC/PD, MTC): 4 Samples analyzed for BRAF mutation: 23/30 (76.6%): samples analyzed for BRAF mutation 4/30 (13%): definite genotype but questioned due to phenotype (ATC/PD, MTC) 2/30 (6%): unable to amplify DNA despite multiple PCR attempts 1/30 (3%): pending analysis 18/30 samples analyzed for RAS mutation, all WT copies of the gene
Slide 25 - Results of Stage 1 Analysis N=22 (interim analysis) 13 WT BRAF 9 BRAF V600E 16 PTC 9 WT BRAF, 7 V600E 6 FTC 4 WT BRAF, 2 V600E
Slide 26 - BRAF V600E P<0.02 N=13 (WT=8, V600E=5)
Slide 27 - Updated genetics In our expanded analysis to 22 pts with WDTC, the effect is no longer significant but the trend exists. We are further investigating BRAF copy number in these patients p=NS N =22 WT = 13 BRAF V600E = 9
Slide 28 - Overview Background Hypothesis Methods Results Discussion Conclusions & Future Directions
Slide 29 - BRAFV600E Correlates with worse Survival Elisei et. al, J Clin Endocrinol Metab, October 2008, 93(10):3943–3949
Slide 30 - BRAFV600E Correlates with worse SurvivalState of the mutation in PTC, 10/2008
Slide 31 - THE BRAF connection Ciampi et al. 2005
Slide 32 - Updated genetics In our expanded analysis to 22 pts with WDTC, the effect is no longer significant but the trend exists. We are further investigating BRAF copy number in these patients p=NS N =22 WT = 13 BRAF V600E = 9
Slide 33 - BRAF (red) x 3 7 centromere (green) x 3
Slide 34 - BRAF x4 7 centromere x4
Slide 35 - 4 copies each 3 copies each
Slide 36 - THE BRAF connection! Positive Predictor! Ciampi et al, 2005.
Slide 37 - Summary Good progression free survival in patients treated with Sorafenib. BRAF V600E appears to predict for improved outcome in patients treated with sorafenib. BRAF copy number gain may explain improved outcome of patients with FTC over patients with PTC
Slide 38 - Future Directions Completion of genotyping analysis of all patients Evaluation of copy number gains in WDTC Hypothesis: Copy number gain accounts for improved survival in FTC treated with Sorafenib Null: Copy number gain does not influence survival in FTC
Slide 39 - Selected Sources Ciampi R, Zhu Z, Nikiforov YE. BRAF copy number gain in thyroid tumors detected by fluorescence in situ hybridization. Endocrine Pathology 2005; 16(2): 99-105. Ciampi R, Nikiforov YE. Alterations of the BRAF gene in thyroid tumors. Endocrine Pathology 2005; 16:3): 163-171. Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II Trial of Sorafenib in Advanced Thyroid Cancer. Journal Clin Onc 2008; 26 (29): 4714-4719. Kundra P, Burman KD. Thyroid Cancer Molecular Signaling Pathways and Use of Targeted Therapy. Endoc Metab Clin N Am 2007;36: 839-853 Murer B. Targeted Therapy in Non-Small Cell Lung Cancer. Arch Path Lab Med. 2008; 132: 1573-1575. Nikiforov YE. Thyroid Carcinoma: Molecular Pathways and Therapeutic targets. Modern Pathology 2008; 21: S37-S43. Vasko V, Ferrand M, Cristofaro JD et al. Specific Pattern of RAS Oncogene Mutations in Follicular Thyroid Tumors. J. Clin Endocrin. & Metab. 2003; 88(6):2745-2752. Xing M. BRAF Mutation in Papillary Thyroid Cancer: Pathogenic Role, Molecular Basis, and Clinical Implication. End Rev 2007; 28(7): 742-762.
Slide 40 - Thanks Marcia Brose, MD PhD Cathy Ma MD, PhD Kanchan Puttaswamy, MS