CYP450 2D6 and Tamoxifen Metabolism. w w w. a u t o g e n o m i c s. c o m

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1 CYP450 2D6 and Tamoxifen Metabolism

2 Tamoxifen Therapy and Breast Cancer: The CYP450 2D6 Connection Morphology of breast cancer associated with BRCA1 mutations. The tumor (to the right of the picture) shows pushing margins (broad, smooth edge to the tumor) and a prominent lymphocytic infiltrate (small blue nuclei).

3 Tamoxifen Therapy Tamoxifen (Nolvadex ) interferes with the activity of estrogen (a hormone). Tamoxifen has been used for more than 20 years to treat patients with advanced breast cancer. It is used as adjuvant, or additional, therapy following primary treatment for early stage breast cancer. In women at high risk of developing breast cancer, Tamoxifen reduces the chance of developing the disease. 1 Tamoxifen is only given for a maximum of 5 years. 3.4 million prescriptions (2002) 1.

4 CYP450 2D6 Connection With Tamoxifen Metabolism Tamoxifen is is metabolized to to its its active active metabolite, Endoxifen primarily via via the the pathways indicated by by the the bold bold arrows arrows shown shown below. below. Endoxifen concentrations are are typically 5-10X 5-10X higher higher than than 4-OH 4-OH TAM. TAM. 1. Y. Jin, D. Flockhart, CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment, J. Nat.Canc. Inst., Vol.97, No.1, Jan.5, P

5 2D6 Tamoxifen FDA Pharmaceutical Advisory Sub-Committee rmscience October 18-19, 2006 Clinical Pharmacology Subcommittee Meeting Executive Summary Tamoxifen%20Background%20Summary%20Final.pdf Meeting On Oct. 18 th, 2006 Quote from the executive summary: at the Annual ASCO Meeting in June 2006 showed that the 3-year relapse-free survival was 68% in patients who are poor metabolizers of CYP2D6 and patients on strong inhibitors of CYP2D6 compared to 98% in patients who are extensive metabolizers of CYP2D6.

6 Meeting Summary Advisory Committee Pharmaceutical Science Does the clinical evidence demonstrate that postmenopausal women with ER-positive breast cancer who are CYP2D6 poor metabolizer (by genotype or drug interaction) are at increased risk for breast cancer recurrence? The consensus of the subcommittee is: the label should be updated to reflect the increased risk for breast cancer along with the mechanistic data presented

7 2D6 Genotypes and Tamoxifen Some CYP450 2D6 variants may impact the metabolism of tamoxifen to its active metabolite, endoxifen Variants of 2D6 *3, *4, *5, *6 Heterozygous or homozygous Significantly Reduced Plasma Endoxifen Concentrations 1 Allele Frequency» 2D6 *4 18.0%» 2D6 *5 2.3% 1. Y. Jin, D. Flockhart, CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment, J. Nat.Canc. Inst., Vol.97, No.1, Jan.5, P

8 2D6 Genotypes and Tamoxifen Many 2D6 variants may have an impact on Tamoxifen metabolism CYP450 2D6 Variant Activity: 2 Alleles with NO enzymatic activity» 2D6 *3, *4, *5del, *6, *7, *8, *11 -*16, *18 -*20, *38, *40, *42, *44 Alleles with Reduced enzymatic activity» 2D6 *9, *10, *17, *29, *36, *37, *41 Alleles with Multiple copies (High activity)» 2D6 *1, *2, *35, *41 2. Borges, S. et al., Quantititative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment, Clin. Pharmacology and Therapeutics, Vol.80., No.1, 2006, P

9 INFINITI 2D6 Tamoxifen* INFINITI 2D6 Tamoxifen Variants Detected: *1, *2, *3, *4, *5-Del, *6, *7, *8, *9, *14, *29, *41A * INFINITI 2D6 Assay is For Research Use Only (RUO)

10 2D6 Genotypes and Tamoxifen It follows that an improved understanding of factors that influence CYP2D6 activity in breast cancer patients and its consequences on endoxifen formation is important to the rational optimization of tamoxifen therapy Borges, S. et al., Quantititative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment, Clin. Pharmacology and Therapeutics, Vol.80., No.1, 2006, P

11 2D6 Genotypes and Tamoxifen With 2D6 Inhibitors Among subjects who carried a homozygous wild type genotype, the mean plasma endoxifen concentration for those who were using CYP2D6 inhibitors was 58% lower than that for those who were not. 1 SSRI Strong 2D6 Inhibitors Paroxetine Fluoxetine 1. Y. Jin, D. Flockhart, CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment, J. Nat.Canc. Inst., Vol.97, No.1, Jan.5, P

12 Summary Tamoxifen is widely used to treat estrogen receptor positive breast cancer 2D6 Variants Reduce Tamoxifen s Active Metabolite (Endoxifen) Reduced Endoxifen, Increases Chances of Breast Cancer Relapse 2 Strong 2D6 Inhibitors, Reduce Endoxifen Levels Paroxetine Fluoxetine The INFINITI CYP 450 2D6T Assay Is Automated By The 510(k) Cleared INFINITI Analyzer.