Pharmacogenetics of Tamoxifen An Pharmacogenetics of Tamoxifen An FDA PerspectiveFDA 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 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: StatisticsBREAST 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 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: IndicationsTamoxifen: 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 Hormonal Therapies of Breast CancerCancer

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 TamoxifenMetabolic Pathway of Tamoxifen

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

CYP2D6 PolymorphismCYP2D6 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 PolymorphismCYP2D6 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 Scientific Evidence: CYP2D6 and Tamoxifen MetabolismTamoxifen 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 Scientific Evidence: CYP2D6 and Tamoxifen MetabolismTamoxifen 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 Clinical Evidence: Tamoxifen Pharmacogenetics and Clinical Pharmacogenetics and Clinical OutcomeOutcome

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

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

Stockholm Breast Cancer GroupPatients: 226Follow-Up: 0.24 to 18.6 yearsMethodology: Variant alleles of CYP2D6 and SULT1A1 genes were assessed by PCREndpoint: Distance recurrence-free survival

Clinical Evidence: Wegman et al. Clinical Evidence: Wegman et al. Breast Cancer Research, 2005Breast 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. Wegman et al. Breast Cancer Res, 2005Breast 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, 2005Breast 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 CenterPatients: 337Follow-Up:11 yearsMethodology: Variant alleles of CYP2D6,SULT1A1 and UGT2B15 genes were assessed by various methodsEndpoints: Overall survival and Progression-free survival

Clinical Evidence: Nowell et al.Clinical Evidence: Nowell et al.Breast Cancer Research and Treatment, 2005Breast 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.Nowell et al.Breast Cancer Research and Treatment 2005Breast 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.Clinical Evidence: Goetz et al.Journal of Clinical Oncology, 2005Journal 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 Clinical Evidence: The impact of CYP2D6 inhibitorsCYP2D6 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 Clinical Evidence: Tamoxifen pharmacogenetics in the prevention pharmacogenetics in the prevention

settingsetting

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 FDA’S Commitment to Personalized MedicinePersonalized 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 TestsAvailability 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 TestsAvailability of the CYP2D6 Tests

National LaboratoriesLabCorpQuest DiagnosticsDNA Vision (EU)

Research CentersMayo ClinicLouisville Lab

OthersApplied BiosystemsBiotageGentrisJurilab (EU)IMGM (EU)Geneblitz (EU)

Empirical Evidence in LabelEmpirical 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 TodayObjectives 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 SubcommitteeQuestions to the Subcommittee

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

Discussion

2. 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 SubcommitteeQuestions to the Subcommittee

3. 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 SubcommitteeQuestions 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 YOUTHANK YOU

BACK UP SLIDESBACK UP SLIDES

Clinical Evidence: Fritz et al.Clinical Evidence: Fritz et al. J Clinical Oncology 2001, 19(1):3-9J 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: 179Follow-Up: 2 to 143 months; Median 91 monthsEndpoint: Overall survivalResults: 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.Fritz et al. J Clinical Oncology 2001, 19(1):3-9J 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