1. Emerging Concepts in the Workup of Melanoma APMG Pathologist, MD FCAP

2. Melanoma Leading cause of death from skin disease ~50% harbor a mutation in the BRAF gene that drives proliferation New York Times in Feb 2010 ran a three part series on a drug in trials (PLX4032) that showed dramatic results in patients with advanced melanoma The drug targets BRAF, shutting it down

3. August 17, 2011

4. Phase 3 Trial Results

5. BRAF and V600 BRAF gene codes for a protein in the epithelial growth factor receptor (EGFR) pathway About 50% of melanomas – Acquired mutation - the pathway is continually activated driving proliferation Most common mutation: V600E – Mutation in DNA causes change in protein amino acid sequence: Valine at amino acid 600 to GlutaminE Second common mutation: V600K – Same amino acid – Valine to Lysine

6. Vemurafenib (Zelboraf®) Package Insert

7. Testing Either primary or metastatic tissue – Formalin-fixed paraffin-embedded (FFPE) Performed using PCR – Very good analytic sensitivity - about 1% – Detects the BRAF mutation with less than 5% tumor cells in the tissue. – More sensitive than sequencing Can be significant in samples with low amount of tumor

8. Questions Contact pathologist with questions or to request testing on a patient: AMPG Pathologist, MD FCAP tlpath@domain.com (888) 555-1212

9. About these slides Provided by the CAP as an aid to pathologists Intended as a “starting point” from which customization / modifications can be made for personal use CAP requests to be notified when the presentation has been used via email to spec@cap.orgspec@cap.org Content has been reviewed by experts at the CAP, but does not necessarily reflect the official opinion of the College of American Pathologists. Version 1.0.1, rev. 4/26/2012 To obtain the latest version of this presentation, visit: http://www.cap.org/spec http://www.cap.org/spec