Pharmacogenetics of tamoxifen an fda perspective
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Pharmacogenetics of Tamoxifen An FDA Perspective. Clinical Pharmacology Subcommittee October 18, 2006 Rockville, Maryland. NAM Atiqur Rahman, Ph.D. Director Division of Clinical Pharmacology 5 Office of Clinical Pharmacology Office of Translational Sciences CDER, FDA.

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Pharmacogenetics of Tamoxifen An FDA Perspective

Clinical Pharmacology Subcommittee October 18, 2006Rockville, Maryland

NAM Atiqur Rahman, Ph.D.Director

Division of Clinical Pharmacology 5

Office of Clinical Pharmacology

Office of Translational SciencesCDER, FDA


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BREAST CANCER: Statistics

Jemal A, et al. CA Cancer J Clin 2006; 56:106-30


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BREAST CANCER: Statistics

  • Probability of developing cancer is higher for men (46%) than for women (38%)

  • Because of the early age of onset of breast cancer, women have higher probability of developing cancer before the age of 60

Jemal A, et al. CA Cancer J Clin 2006; 56:106-30


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BREAST CANCER: Statistics

Jemal A, et al. CA Cancer J Clin 2006; 56:106-30



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Hormonal Therapies of Breast Cancer

  • Selective Estrogen Receptor Modulator

    • Tamoxifen

  • Aromatase Inhibitors

    • Anastrazole (Arimidex)

    • Letrozole (Femara)

    • Exemestane (Aromasin)

      Only Tamoxifen is approved for breast cancer risk reduction in high risk women


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Metabolic Pathway of Tamoxifen

Goetz, et al. J Clin Oncol 2005; 23:9312-18


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CYP2D6 Polymorphism

  • Gene located in chromosome 22

  • Four Distinct Phenotypes: UM, EM, IM and PM

  • 5-10% of Caucasians are PMs, and 10-15% are IMs

  • Approximately 12 alleles confer poor metabolizer phenotype


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CYP2D6 Polymorphism

Bradford, L.D. Pharmacogenomics 2002; 3:229-243


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Scientific Evidence: CYP2D6 and Tamoxifen Metabolism

List of Publications

  • Lien EA, et al. Cancer Res 1989, 49:2175-2183

  • Sridar C, et al. J Pharmacol Exp Ther 2002, 301:945-52

  • Coller JK, et al. Br J Clin Pharmacol 2002, 54:157-167

  • Stearns V, et al. J Natl Cancer Inst 2003, 95:1758-64

  • Johnson MD, et al. Breast Cancer Res Treat 2004, 85:151-9

  • Desta Z, et al. J Pharmacol Exp Ther 2004, 10:1062-75


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Scientific Evidence: CYP2D6 and Tamoxifen Metabolism

List of Publications

  • Gjerde J, et al. Breast Can Res Treat 94:S236, 2005

  • Jin Y, et al. J Natl Cancer Inst 2005, 97:30-9

  • Borges S, et al. Clin Pharmacol Ther 2006, 80:61-74

  • Lim YC, et al. J Pharmacol Exp Ther 2006, 18:503-12


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Clinical Evidence: Tamoxifen Pharmacogenetics and Clinical Outcome

List of Publications

  • Goetz M, et al. Breast Cancer Res Treat 2006 ( in press)

  • Bonanni B, et al. J Clin Oncol 2006, 24:3708-9

  • Goetz M, et al. J Clin Oncol 2005, 23:9312-8

  • Wegman P, et al. Breast Cancer Res 2005, 7:284-90

  • Nowell S, et al. Breast Cancer Res Treat 2005, 91:249-58

  • Assie et al. Cancer Epidem Bio Prev 2002, 11:1697-1698

  • Fritz P et al. J Clin Oncol 2001, 19:3-9


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Clinical Evidence: Wegman et al. OutcomeBreast Cancer Research, 2005

Genotype of Metabolic enzymes and the Benefit of Tamoxifen in Postmenopausal Breast Cancer Patients

Stockholm Breast Cancer Group

Patients: 226

Follow-Up: 0.24 to 18.6 years

Methodology: Variant alleles of CYP2D6 and SULT1A1 genes were assessed by PCR

Endpoint: Distance recurrence-free survival


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Clinical Evidence: Wegman et al. OutcomeBreast Cancer Research, 2005

Results:

1. Patients with CYP2D6 *4 variant allele treated with tamoxifen (24) had a decreased recurrence rate compared to patients not treated with tamoxifen (n=23).

2. Patients with wild type SULT1A1 gene had decreased recurrence rate when treated with tamoxifen

Conclusions: Results contradicts prior hypothesis. need to be confirmed in a larger cohort


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Wegman et al. OutcomeBreast Cancer Res, 2005

  • Do Know

    • 40 mg/day of tamoxifen treatment for 2 years

    • Tamoxifen activity was tested against chemotherapy and radiotherapy

    • Limited number (n=4) of ER+ breast cancer patients with CYP2D6*4/*4 allele

  • Don’t Know

    • Tamoxifen for 5 years

    • Effect of tamoxifen on patients with PM phenotype alone

    • Impact of chemotherapy and radiotherapy on clinical outcome

    • Potential effects of concomitant medications (CYP2D6 inhibitors)

    • Why patients with SULT1A1 normal activity alleles have better clinical outcome?


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Clinical Evidence: Nowell et al. OutcomeBreast Cancer Research and Treatment, 2005

Association of Genetic Variation in Tamoxifen-Metabolizing Enzymes with Overall Survival and Recurrence of Disease in Breast Cancer Patients

Arkansas Cancer Research Center

Patients: 337

Follow-Up:11 years

Methodology: Variant alleles of CYP2D6,SULT1A1 and UGT2B15 genes were assessed by various methods

Endpoints: Overall survival and Progression-free survival


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Clinical Evidence: Nowell et al. OutcomeBreast Cancer Research and Treatment, 2005

Results:

1. No association between CYP2D6 genotype and overall survival.

2. UGT2B15 high activity genotypes had increased risk of recurrence and poorer survival

3. Two “at-risk” alleles of UGT2B15 and SULT1A1 genes have poorer survival on tamoxifen

Conclusions: Genetic variation of phase 2 enzymes can influence efficacy of tamoxifen therapy in breast cancer


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Nowell et al. OutcomeBreast Cancer Research and Treatment 2005

  • Do Know

    • Genetic variations of two phase 2 enzymes (SULT1A1 and UGT2B15) may impact clinical outcome when treated with tamoxifen

    • No association between CYP2D6 genotype clinical outcome

  • Don’t Know

    • Effect of tamoxifen on patients with PM phenotype alone

    • Impact of chemo and radiation on the overall clinical outcome (only 48 patients (14%) received tamoxifen alone)

    • The impact of CYP2D6*4/*4 genotype on clinical outcome

    • Potential effects of concomitant medications (CYP2D6 inhibitors)


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Clinical Evidence: Goetz et al. OutcomeJournal of Clinical Oncology, 2005

  • NCCTG prospective cooperative group adjuvant tamoxifen trial in surgically treated ER positive breast cancer (n=256)

  • Methodology: Variant CYP2D6 alleles (*4,*6) retrospectively assessed in 190 pts

  • Results: In a multivariate analysis, women with the CYP2D6 *4/*4 genotype tended to have worse RFS and DFS


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Clinical Evidence: The impact of CYP2D6 inhibitors Outcome

  • Endoxifen plasma levels are affected by CYP2D6 genetic variation and CYP2D6 inhibitors

  • In an updated analysis, women with impaired CYP2D6 metabolism (genotype and inhibitors) had significantly worse clinical outcome independent of standard prognostic factors

  • The effect of impaired metabolism was greatest in CYP2D6 PM (HR 2.69, p=0.005)

Goetz et al. Breast Cancer Research Treatment (In Press)


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Clinical Evidence: Tamoxifen pharmacogenetics in the prevention setting

  • Italian Chemoprevention Trial study

  • The frequency of the CYP2D6*4/*4 genotype was significantly higher in tamoxifen-treated women who developed breast cancer than in women who did not develop breast cancer (p=0.015)

Bonnani et al. Journal of Clinical Oncology. 2006;


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FDA’S Commitment to Personalized Medicine prevention setting

“ I believe we are moving into a remarkable and powerful new era in medicine and particularly in prescription drugs. I’d refer to it as an era of personalized medicine.”

Michael Leavitt – January 18, 2005


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Availability of the CYP2D6 Tests prevention setting

AmpliChip CYP450 Test is an FDA approved Test

29 variant alleles of CYP2D6 and CYP2C19 are detected

Reproducibility : 99.7% (genotype calls)

99.9% (correct calls)

Precision: 100%


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Availability of the CYP2D6 Tests prevention setting

  • National Laboratories

    LabCorp

    Quest Diagnostics

    DNA Vision (EU)

  • Research Centers

    Mayo Clinic

    Louisville Lab

  • Others

    Applied Biosystems

    Biotage

    Gentris

    Jurilab (EU)

    IMGM (EU)

    Geneblitz (EU)


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Empirical Evidence in Label prevention setting

  • Dose Adjustment in Drug Label

    Age (elderly and pediatrics)

    Bilirubin status

    Renal function

    Cardiac conditions

    Performance status

    Food intake

    Concomitant medications


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Objectives for Today prevention setting

  • Discuss the scientific and clinical evidence linking CYP2D6 polymorphism with response to tamoxifen therapy

  • Discuss the role that CYP2D6 testing can play in identifying post-menopausal breast cancer patients who should receive tamoxifen in adjuvant setting


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Questions to the Subcommittee prevention setting

  • The scientific evidence on the metabolism of tamoxifen demonstrates that CYP2D6 is an important pathway in the formation of endoxifen.

    Discussion

  • The pharmacologic and clinical evidence are sufficient to demonstrate that endoxifen significantly contributes to the pharmacologic (anti-estrogenic) effect of tamoxifen.

    Discussion


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Questions to the Subcommittee prevention setting

  • Does the clinical evidence demonstrate that postmenopausal women with ER-positive breast cancer who are CYP2D6 poor metabolizer are at increased risk for breast cancer recurrence?

    If yes, should the tamoxifen label include information about increased risk for breast cancer recurrence in CYP2D6 poor metabolizers prescribed tamoxifen?

    If not, what additional types of clinical evidence will demonstrate that postmenopausal women with ER- positive breast cancer who are CYP2D6 poor metabolizer may be at increased risk for breast cancer recurrence?


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Questions to the Subcommittee prevention setting

4. Is there sufficient scientific and clinical evidence to support revisions of the tamoxifen label that recommends CYP2D6 genotype testing for post-menopausal patients before they are prescribed tamoxifen for adjuvant treatment?


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THANK YOU prevention setting


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BACK UP SLIDES prevention setting


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Clinical Evidence: Fritz et al. prevention settingJ Clinical Oncology 2001, 19(1):3-9

Microsomal Epoxide Hydrolase as a Predictor of Tamoxifen Response in Primary Breast Cancer: A Retrospective Study with Long-Term Follow –Up

Stuttgart, Germany

Patients: 179

Follow-Up: 2 to 143 months; Median 91 months

Endpoint: Overall survival

Results: Expression of mEH was correlated with poor disease outcome in all patients (p < 0.01) and in patients treated with tamoxifen (*p < 0.01; n= 78)

Conclusions: mEH may be a novel prognostic factor for survival when treated with tamoxifen

* Log-Rank Test


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Fritz et al. prevention settingJ Clinical Oncology 2001, 19(1):3-9

  • Do Know

    • Over-expression of mEH may predispose for poor outcome

    • Patients were treated for adjuvant as well as for palliation

  • Don’t Know

    • Relationship between mEH expression and CYP2D6 polymorphism

    • Binding affinity of endoxifen to AEBS

    • Assay sensitivity and expression categories


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