1. 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

2. 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

3. 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

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

5. 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

6. 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

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

8. 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

9. 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:

10. Scientific Evidence: CYP2D6 and Tamoxifen Metabolism
List of Publications
Lien EA, et al. Cancer Res 1989, 49:
Sridar C, et al. J Pharmacol Exp Ther 2002, 301:945-52
Coller JK, et al. Br J Clin Pharmacol 2002, 54:
Stearns V, et al. J Natl Cancer Inst 2003, 95:
Johnson MD, et al. Breast Cancer Res Treat 2004, 85:151-9
Desta Z, et al. J Pharmacol Exp Ther 2004, 10:

11. 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

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

13. 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

14. 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

15. 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?

16. 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

17. 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

18. 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)

19. 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

20. 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)

21. 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;

22. 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

23. 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%

24. 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)

25. 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

26. 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

27. 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.

28. 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?

29. 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?

30. THANK YOU

31. BACK UP SLIDES

32. 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

33. 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