tamoxifenpharmacogenetics
Transcript of 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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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 ofdeveloping cancer before the age of 60
Jemal A, et al. CA Cancer J Clin 2006; 56:106-30
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BREAST CANCER: StatisticsBREAST CANCER: Statistics
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%
Jemal A, et al. CA Cancer J Clin 2006; 56:106-30
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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
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
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Clinical Evidence: TamoxifenClinical Evidence: Tamoxifen
Pharmacogenetics and ClinicalPharmacogenetics and Clinical
OutcomeOutcome
List of Publications
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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Questions to the SubcommitteeQuestions to the Subcommittee
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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Questions to the SubcommitteeQuestions to the Subcommittee
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
categories