# Presentation: 888252

## Pharmacogenetics of Tamoxifen An FDA Perspective

- NAM Atiqur Rahman, Ph.D.Director
- Division of Clinical Pharmacology 5
- Office of Clinical Pharmacology
- Office of Translational SciencesCDER, FDA

- Clinical Pharmacology Subcommittee October 18, 2006Rockville, Maryland

## 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% | 75% |
| 1983-1985 | 79% | 64% | 78% |
| 1995-2001 | 90% | 76% | 88% |

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

## Tamoxifen: Indications

| 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 | None | 2-4% | 6-7% | 5-6% |
| *6 | None | 1% | <1% | N/A |
| *10 | Reduced | 4-8% | 3-8% | 39-41% |
| *17 | Reduced | N/A | 15-26% | N/A |

***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.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.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.**
**	****Discussion **

## 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**
**	**