research presentation
Download
Skip this Video
Download Presentation
Research Presentation

Loading in 2 Seconds...

play fullscreen
1 / 39

Research Presentation - PowerPoint PPT Presentation


  • 86 Views
  • Uploaded on

Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870. Research Presentation. Jason M. Leibowitz, MD June 25, 2009 Preceptor: Marcia S. Brose, MD PhD . Overview. Background Hypothesis Methods Results Discussion

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Research Presentation' - artie


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
research presentation
Otorhinolaryngology: Head and Neck Surgery at PENN

Excellence in Patient Care, Education and Research since 1870

Research Presentation

Jason M. Leibowitz, MD

June 25, 2009

Preceptor: Marcia S. Brose, MD PhD

overview
Overview
  • Background
  • Hypothesis
  • Methods
  • Results
  • Discussion
  • Conclusions & Future Directions
thyroid cancer in the united states
Thyroid cancer is themost commonendocrine 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.

Thyroid Cancer in the United States
rai refractory disease
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.
molecular pathway involved in thyroid cancer
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.

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

BRAF V600E in Thyroid Cancer
braf v600e
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.
slide9
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).
targeted therapy in thyroid cancer
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
sorafenib
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.
targeted therapy and genotype
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.
prior data
Prior Data

84 weeks

N=43

WDTC

N= 52

papillary vs follicular
Papillary vs. Follicular

FTC = 19

PTC= 24

P<0.095

prior data15
Prior Data
  • Conclusions from prior data:
    • Improved PFS with Sorafenib.
    • Improved PFS of FTC treated with Sorafenib when compared to PTC.
overview16
Overview
  • Background
  • Hypothesis
  • Methods
  • Results
  • Discussion
  • Conclusions & Future Directions
hypothesis
Hypothesis
  • There are specific genotypes (i.e. BRAF V600E, RAS mutations) that predict favorable response to targeted therapy (Sorafenib).
null hypothesis
Null Hypothesis
  • Specific genetic mutations do not predict response to targeted therapy in thyroid cancer.
overview19
Overview
  • Background
  • Hypothesis
  • Methods
  • Results
  • Discussion
  • Conclusions & Future Directions
research plan
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
sequence output
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

overview23
Overview
  • Background
  • Hypothesis
  • Methods
  • Results
  • Discussion
  • Conclusions & Future Directions
results of stage 1 analysis
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
results of stage 1 analysis25
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
braf v600e26
BRAF V600E

P<0.02

N=13 (WT=8, V600E=5)

updated genetics
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

N =22

WT = 13

BRAF V600E = 9

p=NS

overview28
Overview
  • Background
  • Hypothesis
  • Methods
  • Results
  • Discussion
  • Conclusions & Future Directions
brafv600e correlates with worse survival
BRAFV600E Correlates with worse Survival

Elisei et. al, J Clin Endocrinol Metab, October 2008, 93(10):3943–3949

the braf connection
THE BRAF connection

Ciampi et al. 2005

updated genetics32
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

N =22

WT = 13

BRAF V600E = 9

p=NS

slide33
BRAF (red) x 3

7 centromere (green) x 3

slide34
BRAF x4

7 centromere x4

slide35
4 copies each

3 copies each

future directions
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
selected sources
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.
thanks
Thanks
  • Marcia Brose, MD PhD
    • Cathy Ma MD, PhD
    • Kanchan Puttaswamy, MS
ad