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

BREAST CANCER: Statistics Estimated New Breast Cancer Cases and Deaths Year 2006 Female Male Both Estimated New Cases 212,920 1,720 214,640 Estimated Deaths 40,970 460 41,430 Jemal A, et al. CA Cancer J Clin 2006; 56:106-30

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

BREAST CANCER: Statistics Trends in Five-Year Survival Rates, 1974-2001 Caucasian African American All Races 1974-1976 75% 63% 1983-1985 79% 64% 78% 1995-2001 90% 76% 88% Jemal A, et al. CA Cancer J Clin 2006; 56:106-30

Tamoxifen: Indications Year of Approval Metastatic Breast Cancer (postmenopausal) 1977 Adjuvant Breast Cancer (postmenopausal node +) 1986 Metastatic Breast Cancer (premenopausal) 1989 Adjuvant Breast Cancer (postmenopausal node -) 1990 Metastatic Breast Cancer (male) 1993 Reduction in Breast Cancer Incidence 1998 Ductal Carcinoma in Situ (DCIS) 2000

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

Metabolic Pathway of Tamoxifen Goetz, et al. J Clin Oncol 2005; 23:9312-18

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

CYP2D6 Polymorphism Allele Enzyme Activity Caucasian African American Japanese *4 None 18-23% 7-9% <1% *5 2-4% 6-7% 5-6% *6 1% N/A *10 Reduced 4-8% 3-8% 39-41% *17 15-26% Bradford, L.D. Pharmacogenomics 2002; 3:229-243

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

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

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

Clinical Evidence: Wegman et al. Breast 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

Clinical Evidence: Wegman et al. Breast 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

Wegman et al. Breast 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?

Clinical Evidence: Nowell et al Clinical Evidence: Nowell et al. Breast 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

Clinical Evidence: Nowell et al Clinical Evidence: Nowell et al. Breast 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

Nowell et al. Breast 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)

Clinical Evidence: Goetz et al. Journal 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

Clinical Evidence: The impact of CYP2D6 inhibitors 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)

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;

FDA’S Commitment to Personalized Medicine “ 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

Availability of the CYP2D6 Tests 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%

Availability of the CYP2D6 Tests 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)

Empirical Evidence in Label Dose Adjustment in Drug Label Age (elderly and pediatrics) Bilirubin status Renal function Cardiac conditions Performance status Food intake Concomitant medications

Objectives for Today 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

Questions to the Subcommittee 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.

Questions to the Subcommittee 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?

Questions to the Subcommittee 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?

THANK YOU

BACK UP SLIDES

Clinical Evidence: Fritz et al. J 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

Fritz et al. J 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