1. Pharmacogenetics and the Management of Breast Cancer: Optimization of Tamoxifen Therapy Mark E. Sobel, M.D., Ph.D. Executive Officer American Society for Investigative Pathology Association for Molecular Pathology mesobel@asip.org 2009 Mid-Atlantic Bio November 6, 2009 This presentation will be available at http://www.asip.org/about/exec.htm http://www.asip.org/about/exec.htm

2. Goals of Personalized Medicine   50% of first treatments do not work   Optimize treatment for individual patients   Minimize adverse drug events   Maximize drug efficacy   Develop more targeted drugs   The right drug at the right dose

3. Application to Oncology   Determine the preferred therapeutic agent for each tumor   Ascertain which patients are most likely to benefit from a given therapy

4. Patients with same diagnosis Adapted, Courtesy Slide from Howard L. McLeod Institute for Pharmacogenomics and Individualized Therapy UNC – Chapel Hill, NC

5. All patients with same diagnosis Toxic Responder: Lower dose or alternate drug

6. All patients with same diagnosis Non-Responder: higher dose or alternate drug

7. Pharmacogenetics: The Study of Variations in Genes that Affect Responses to Drugs Genetic changes specifically within malignant tumor cells Inherited genetic variability in a targeted gene or group of functionally-related genes affecting response to drugs

8. Pharmacogenetics: The Study of Variations in Genes that Affect Responses to Drugs Genetic changes specifically within malignant tumor cells Estrogen Receptor Status Treatment with SERMs- selective ER modulators Tamoxifen Raloxifene Multigene analysis: OncoType DX assay (21 genes) MammaPrint assay (70 genes) Epidermal growth factor receptor (EGFR) Status HER2/neu (Herceptin therapy)

14. Pharmacogenetics: The Study of Variations in Genes that Affect Responses to Drugs Genetic changes specifically within malignant tumor cells Inherited genetic variability in a targeted gene or group of functionally-related genes affecting response to drugs

15. Pharmacokinetics: What the Body Does to the Drug Absorption – substance enters the body Distribution – drug disperses to fluids and tissues Metabolism – transform parent compound into daughter compounds Excretion – elimination of parent drug and daughter compounds from the body

16. Pharmacokinetic Metabolism: Pharmacokinetic Metabolism: transform parent compound into daughter metabolites Parent compounds are converted to metabolites that are more water soluble so they can be more easily excreted Bioactivation: Prodrugs are converted into therapeutically active compounds

17. Cytochrome P450 Enzymes Supergene family Active in the liver and small intestine Named for the characteristic absorption spectra of the protein products (450 nm) Human genome: 57 CYP genes 15 genes involved in metabolism of xenobiotics 75% of total metabolism of drugs 14 genes involved in metabolism of sterols 4 genes oxidize fat-soluble vitamins 9 involved in metabolism of fatty acids and eicosanoids 15 unknown function

18. CYP 2 D 6 *1 Supergene family Family Subfamily Isoenzyme Allelic variant CYP Nomenclature *1 is usually wild-type

19. Tamoxifen   Approved by the US FDA for the treatment and prevention of breast cancer   Anti-estrogen   SERM: selective estrogen receptor modulator

22. Tamoxifen: A Prodrug Requiring Extensive Metabolism Adapted from Goetz, M. P. et al. J Clin Oncol; 23:9312-9318 2005 Tamoxifen N-desmethylTAM CYP3A4/5 CYP2D6 4-hydroxyTAM CYP2D6 Endoxifen CYP3A4/5 MAJOR METABOLITE- SAME POTENCY MINOR METABOLITE - 100X POTENCY MODERATE METABOLITE- 100X POTENCY Genetic variants of CYP2D6 and drugs that modulate this enzyme significantly affect outcome in tamoxifen-treated patients

23. CYP2D6 and Tamoxifen At least 70 CYP2D6 allelic variants Reduced activity of CYP2D6 → reduced metabolism of tamoxifen → poor response to tamoxifen Classification of alleles Poor metabolizers Intermediate metabolizers Extensive metabolizers Ultrarapid metabolizers Ethnic variation – CYP2D6*4 – poor metabolizer 12% - 21% Northern Europeans 1% - 2% Asians and Black Africans CYP2D6*10 – intermediate metabolizer Most common allele in Asians

24. Tamoxifen Side Effects   Hot flashes   Endometrial cancer   Thromoembolic events

28. Side effects of Tamoxifen and Treatment with Antidepressants Hot flashes most common side effect Treated with antidepressants: SSRIs (selective serotonin reuptake inhibitors) Inhibit CYP2D6 activity Potent inhibitors (paroxetene, fluoxetine) reduce endoxifen levels Less potent inhibitors (venlafaxine) have little effect Patients with decreased metabolism: Shorter time to recurrence Worse relapse-free survival Potent CYP2D6 inhibitors such as certain SSRIs are contraindicated in tamoxifen-treated patients

29. CYP2D6 Poor Metabolizers Patients diagnosed with breast cancer should be treated with alternatives to tamoxifen (e.g. aromatase inhibitors) For breast cancer prevention, raloxifene is a viable alternative to tamoxifen

31. Recommended reading: Snozek CLH, O’Kane DJ, and Algeciras-Schimnich A.: Pharmacogenetics of Solid Tumors: Directed Therapy in reat, Lung, and Colorectal Cancer. J Mol Diagn 2009, 11:381-389, DOI: 10.2353/jmoldx.2009.090003 This presentation will be available at http://www.asip.org/about/exec.htm http://www.asip.org/about/exec.htm