Pharmacogenetics and the Management of Breast Cancer: Optimization of Tamoxifen Therapy

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Pharmacogenetics and the Management of Breast
CancerOptimization of Tamoxifen Therapy

• Mark E. Sobel, M.D., Ph.D.
• Executive Officer
• American Society for Investigative Pathology
• Association for Molecular Pathology
• mesobel_at_asip.org
• 2009 Mid-Atlantic Bio
• November 6, 2009
• This presentation will be available at
  http//www.asip.org/about/exec.htm

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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

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Application to Oncology

• Determine the preferred therapeutic agent for
  each tumor
• Ascertain which patients are most likely to
  benefit from a given therapy

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Patients with same diagnosis
Adapted, Courtesy Slide from Howard L.
McLeod Institute for Pharmacogenomics and
Individualized Therapy UNC Chapel Hill, NC
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All patients with same diagnosis
Toxic Responder Lower dose or alternate drug
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All patients with same diagnosis
Non-Responder higher dose or alternate drug
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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

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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)

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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

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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

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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

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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

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CYP Nomenclature
CYP 2 D 6 1
1 is usually wild-type
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Tamoxifen

• Approved by the US FDA for the treatment and
  prevention of breast cancer
• Anti-estrogen
• SERM selective estrogen receptor modulator

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Tamoxifen A Prodrug Requiring Extensive
Metabolism
4-hydroxyTAM
Tamoxifen
CYP2D6
MINOR METABOLITE - 100X POTENCY
CYP3A4/5
CYP3A4/5
CYP2D6
N-desmethylTAM
Endoxifen
MAJOR METABOLITE- SAME POTENCY
MODERATE METABOLITE- 100X POTENCY
Genetic variants of CYP2D6 and drugs that
modulate this enzyme significantly affect outcome
in tamoxifen-treated patients
Adapted from Goetz, M. P. et al. J Clin Oncol
239312-9318 2005
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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
• CYP2D64 poor metabolizer
• 12 - 21 Northern Europeans
• 1 - 2 Asians and Black Africans
• CYP2D610 intermediate metabolizer
• Most common allele in Asians

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Tamoxifen Side Effects

• Hot flashes
• Endometrial cancer
• Thromoembolic events

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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
  

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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

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• Recommended reading
• Snozek CLH, OKane DJ, and Algeciras-Schimnich
  A. Pharmacogenetics of Solid Tumors Directed
  Therapy in reat, Lung, and Colorectal Cancer. J
  Mol Diagn 2009, 11381-389, DOI
  10.2353/jmoldx.2009.090003
• This presentation will be available at
  http//www.asip.org/about/exec.htm