tamoxifenpharmacogenetics

8/7/2019 tamoxifenpharmacogenetics

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Pharmacogenetics of TamoxifenPharmacogenetics of Tamoxifen

An FDA PerspectiveAn FDA Perspective

NAM Atiqur Rahman, Ph.D.Director

Division of Clinical Pharmacology 5Office of Clinical Pharmacology

Office of Translational SciencesCDER, FDA

Clinical Pharmacology Subcommittee October 18, 2006

Rockville, Maryland


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BREAST CANCER: StatisticsBREAST CANCER: Statistics

Estimated New Breast Cancer Cases and Deaths

Year 2006

Female Male Both

Estimated

New Cases212,920 1,720 214,640

Estimated

Deaths40,970 460 41,430

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


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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 ofdeveloping cancer before the age of 60



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Trends in Five-Year Survival Rates, 1974-2001

Caucasian AfricanAmerican

All Races

1974-1976 75% 63% 75%

1983-1985 79% 64% 78%

1995-2001 90% 76% 88%



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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


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Hormonal Therapies ofBreastHormonal Therapies ofBreast

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


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CYP2D6 PolymorphismCYP2D6 Polymorphism

Gene located in chromosome 22

Four Distinct Phenotypes: UM, EM, IM andPM

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

are IMs

Approximately 12 alleles confer poormetabolizer phenotype


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CYP2D6 PolymorphismCYP2D6 Polymorphism

Allele Enzyme

Activity

Caucasian African

American

Japanese

*4 None 18-23% 7-9%


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Scientific Evidence: CYP2D6 andScientific Evidence: CYP2D6 and

Tamoxifen MetabolismTamoxifen Metabolism

List of Publications

Lien EA, et al. CancerRes 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 CancerRes Treat 2004, 85:151-9

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


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Scientific Evidence: CYP2D6 andScientific Evidence: CYP2D6 and

Tamoxifen MetabolismTamoxifen Metabolism


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: TamoxifenClinical Evidence: Tamoxifen

Pharmacogenetics and ClinicalPharmacogenetics and Clinical

OutcomeOutcome


Goetz M, et al. Breast CancerRes Treat 2006 ( in press)

BonanniB, 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 CancerRes 2005, 7:284-90

Nowell S, et al. Breast CancerRes Treat 2005, 91:249-58

Assie et al. CancerEpidemBio 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.Clinical Evidence: Wegman et al.Breast CancerResearch, 2005Breast CancerResearch, 2005

Genotype of Metabolic enzymes and the Benefit ofTamoxifen in Postmenopausal Breast CancerPatients

Stockholm Breast CancerGroup

Patients: 226

Follow-Up: 0.24 to 18.6 years

Methodology: Variant alleles of CYP2D6 andSULT1A1 genes were assessed by PCR

Endpoint: Distance recurrence-free survival


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Clinical Evidence: Wegman et al.Clinical Evidence: Wegman et al.Breast CancerResearch, 2005Breast CancerResearch, 2005

Results:

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

2. Patients with wild type SULT1A1 gene had

decreased recurrence rate when treated withtamoxifen

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


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Wegman et al.Wegman et al.B

reast CancerR

es, 2005B

reast CancerR

es, 2005 Do Know

40 mg/day of tamoxifen treatment for 2 years

Tamoxifen activity was tested against chemotherapy and

radiotherapy Limited number (n=4) ofER+ breast cancer patients with

CYP2D6*4/*4 allele

Dont Know Tamoxifen for 5 years

E

ffect of tamoxifen on patients with PM phenotype alone Impact of chemotherapy and radiotherapy on clinical

outcome

Potential effects of concomitant medications (CYP2D6inhibitors)

Why patients with SULT1A1 normal activity alleles have

better clinical outcome?


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Clinical Evidence: Nowell et al.Clinical Evidence: Nowell et al.Breast CancerResearch and Treatment, 2005Breast CancerResearch and Treatment, 2005

Association ofGenetic Variation in Tamoxifen-Metabolizing Enzymes with Overall Survival andRecurrence 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 variousmethods

Endpoints:Overall survival and Progression-freesurvival


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Clinical Evidence: Nowell et al.Clinical Evidence: Nowell et al.Breast CancerResearch and Treatment, 2005Breast CancerResearch 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.Nowell et al.Breast CancerResearch and Treatment 2005Breast CancerResearch 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

Dont Know Effect of tamoxifen on patients with PM phenotype alone

Impact of chemo and radiation on the overall clinicaloutcome (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.Clinical Evidence: Goetz et al.Journal of Clinical Oncology, 2005Journal of Clinical Oncology, 2005

NCCTG prospective cooperative group adjuvanttamoxifen 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 withthe CYP2D6 *4/*4 genotype tended to have

worse RFS and DFS


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Clinical Evidence: The impact ofClinical 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)


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Clinical Evidence: TamoxifenClinical Evidence: Tamoxifen

pharmacogenetics in the preventionpharmacogenetics 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. Journalof Clinical Oncology.

2006;


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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%


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Availability of the CYP2D6 TestsAvailability 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)


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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


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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 receivetamoxifen in adjuvant setting


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Questions to the SubcommitteeQuestions to the Subcommittee

1. The scientific evidence on the metabolism oftamoxifen demonstrates that CYP2D6 is animportant pathway in the formation ofendoxifen.

Discussion

2. The pharmacologic and clinical evidence aresufficient to demonstrate that endoxifensignificantly contributes to the pharmacologic(anti-estrogenic) effect of tamoxifen.

Discussion


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3. Does the clinical evidence demonstrate thatpostmenopausal women withER-positive breast cancer whoare CYP2D6 poor metabolizer are at increased risk for breastcancer recurrence?

If yes, should the tamoxifen label include informationabout increased risk for breast cancer recurrence inCYP2D6 poor metabolizers prescribed tamoxifen?

If not, what additional types of clinical evidence will

demonstrate that postmenopausal women withER-positive breast cancer who are CYP2D6 poormetabolizer may be at increased risk for breast cancerrecurrence?


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4. Is there sufficient scientific and clinical

evidence to support revisions of the

tamoxifen label that recommends CYP2D6genotype testing for post-menopausal

patients before they are prescribed

tamoxifen for adjuvant treatment?


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THANK YOUTHANK YOU


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BACK UP SLIDESBACK UP SLIDES


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Clinical Evidence: Fritz et al.Clinical Evidence: Fritz et al.

J Clinical Oncology 2001, 19(1):3J Clinical Oncology 2001, 19(1):3--99

Microsomal Epoxide Hydrolase as a Predictor of TamoxifenResponse in Primary Breast Cancer: A Retrospective Studywith 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 diseaseoutcome in all patients (p < 0.01) and in patients treated withtamoxifen (*p < 0.01; n= 78)

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

* Log-Rank Test


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Fritz et al.Fritz et al.

J Clinical Oncology 2001, 19(1):3J Clinical Oncology 2001, 19(1):3--99

Do Know

Over-expression of mEH may predispose

for poor outcome Patients were treated for adjuvant as well

as for palliation

Dont Know

R

elationship between mEH

expression andCYP2D6 polymorphism

Binding affinity of endoxifen to AEBS

Assay sensitivity and expression

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tamoxifenpharmacogenetics

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