Tamoxifen Pharmacogenetics and Prediction of Breast Cancer Relapse After Administration of Tamoxifen Matthew P. Goetz, MD Assistant Professor of Oncology Mayo Clinic College of Medicine CP David Flockhart, MD, PhD Consortium on Breast Cancer Pharmacogenomics (COBRA) Pharmacogenomics Research Network
Breast Cancer 2006 (USA) Invasive Breast Cancer: 212,920 New Cases Ductal Carcinoma in Situ: 61,980 Cases 2/3 are estrogen positive—Candidates for hormonal therapy Jemal A, et al. CA Cancer J Clin 2006;56;106-30
Tamoxifen The most important drug worldwide for hormone receptor positive breast cancer Approved by the FDA for treatment of High-risk patients DCIS Pre and Postmenopausal breast cancer Metastatic disease Most commonly used hormonal therapy in early and advanced male breast cancer CP
Tamoxifen and Breast Cancer FDA-Approved Indications Postmenopausal Metastatic DCIS ‘86 Adjuvant Postmenopausal Node+ Premenopausal Metastatic ‘89‘90 Adjuvant Node-negative ‘93 Male Metastatic “Prevention” ‘98
CP EBCTCG: Lancet 365:1687, 2005 Recurrence (%) Years Control 45-0% Control 45-0% About 5 years of tamoxifen 33.2% About 5 years of tamoxifen 33.2% Tamoxifen (for ~5 yrs) in Early Breast Cancer Oxford Meta-analysis* *10,386 women Hazard Ratio (Control/Tamoxifen) = ~1.69
Adjuvant Hormonal Therapy: Designs of Recent Major Trials CP Switching Tamoxifen Aromatase Inhibitor Placebo Initial Adjuvant Therapy 5 yr 2-3 yr 5 yr ~5 yr Extended Adjuvant Therapy R R R R R R DFS HR 0.57 DFS HR
Adjuvant hormonal therapy Pre-menopausal Tamoxifen for 5 years Postmenopausal Aromatase inhibitor for 5 years or… Tamoxifen for 2-3 yrs followed by an AI
ATAC: Recurrences before 2.5 years Proportion with recurrence (%) HR95% CIp-value AN vs TAM – * Censoring non-BC deaths before recurrence Time to event (months) No. of Pts. at risk AN TAM Anastrozole Tamoxifen Howell A, EBCC Hamburg Absolute difference 1.6%
Is there a better way to identify patients for whom tamoxifen or anastrozole would be the preferred drug for initial adjuvant endocrine therapy?
Tamoxifen Metabolic Pathway Jin, Y. et al. J Natl Cancer Inst 2005;97:30-39 CP
Endoxifen and 4-OH-Tamoxifen are Equipotent as Inhibitors of Estrogen Stimulated Cell Proliferation Concentration Cell Growth Johnson MD, et al: Breast Cancer Res Treat 85:151-9, 2004
Endoxifen and 4-OH tamoxifen Same potency in ER binding 1 Suppression of ER-dependent MCF-7 proliferation 2 global ER-responsive gene expression 3 Different Endoxifen concentrations 10 fold higher than 4- hydroxy tamoxifen 4 1. Johnson et al. Breast Cancer Res Treat Lim YC, Cancer Chemother Pharmacol 2005;. 3. Lim YC, et al. J Pharmacol Exp Ther 2006;In Press. 4. Stearns Vet al. J Natl Cancer Inst 2003.
Tamoxifen Metabolic Pathway CP Jin Y et al: J Natl Cancer Inst 97:30, 2005
CYP2D6 Genotype and Endoxifen CP Jin Y et al: J Natl Cancer Inst 97:30, 2005 CYP2D6*4 (most common genetic variant associated with the CYP2D6 poor metabolizer state) P<0.001, r 2 =0.24 Plasma Endoxifen (nM)
NCCTG CP RANDOMIZATIONRANDOMIZATION Postmenopausal women Early ER + breast cancer 541 women accrued 5 years tamoxifen + 1 year fluoxymesterone (n=285) 5 years of tamoxifen (n=256) Ingle et al. Breast Cancer Res Treat Mar 15
NCCTG Surgically resected stage I-III breast cancer All tumors were estrogen receptor positive ≥10 fmol/mg cytosol protein positive or positive by immunohistochemical assay No adjuvant chemotherapy allowed Median follow-up of 11 years Accrual completed in April 1995 No differences in RFS or OS Ingle et al. Breast Cancer Res Treat Mar 15
CYP2D6*4 Genotyping Tamoxifen monotherapy arm (256 patients) Formalin-fixed paraffin-embedded tumor blocks (223 patients) CYP2D6*4 (n=190) Wt/Wt – 137 (72%) Wt/*4 – 40 (21%) *4/*4 – 13 (7%) CP Goetz, Rae et al: J Clin Oncol 23:9312, 2005
% % Years after randomization CYP2D6 Wt/Wt Relapse-free Time CYP2D6 *4/Wt CP CYP2D6 *4/*4 P=0.030P=0.030 Goetz et al J Clin Oncol. 2005;23(36):
% % Years after randomization Relapse-free Survival CP CYP2D6 WT/WT CYP2D6 *4/WT P=0.020 CYP2D6 *4/*4 Goetz et al J Clin Oncol. 2005;23(36):
Incidence of Moderate or Severe Hot Flashes Genotype% of patients who developed moderate or severe hot flashes *CYP2D6 *4/*4 *CYP2D6 *4/WT or Wt/WT 0% 20% Goetz et al J Clin Oncol. 2005;23(36):
CYP2D6 *4 Genotype and Clinical Outcome (multivariate analysis) *4/*4 vs Wt/Wt or Wt/*4 Time to breast recurrence: HR* 1.85, p=0.176 Relapse-free survival: HR* 1.86, p=0.089 CP *Adjusted for nodal status, tumor size Goetz, Rae et al: J Clin Oncol 23:9312, 2005
Without Paroxetine With Paroxetine Stearns V, et al. J Natl Cancer Inst 2003;95(23):
Inhibition of CYP2D6 Affects Endoxifen Concentrations CP Jin Y et al: J Natl Cancer Inst 97:30, 2005 Wt/Wt, no inhibitor VenlafaxineSertralineParoxetine*4/*4, no inhibitor Plasma Endoxifen (nM)
CYP2D6 Inhibitors and Breast Cancer Relapse Paroxetine, fluoxetine, and venlafaxine significantly reduce the number and severity of hot flashes in tamoxifen-treated women % tamoxifen-treated patients are prescribed antidepressants for depression or hot flashes 4 Other commonly administered medications also inhibit CYP2D6 (amiodarone, doxepin, cimetidine) An analysis of CYP2D6 metabolism in tamoxifen treated patients is incomplete without accounting for CYP2D6 inhibitors CP Loprinzi CL et al. Lancet 2000;356:2059– Loprinzi CL, et al. J Clin Oncol 2002;20:1578– Stearns et al. JAMA 2003;289:2827– Love et al. Patterns of Care in Medical Oncology (2005)
NCCTG CP RANDOMIZATIONRANDOMIZATION Postmenopausal women Early ER + breast cancer 541 women accrued 5 years tamoxifen + 1 year fluoxymesterone (n=285) 5 years of tamoxifen (n=256) Ingle et al. Breast Cancer Res Treat Mar 15
Methods 225 Charts were reviewed at each randomizing site to ascertain medication history Potent CYP2D6 inhibitors: Fluoxetine and paroxetine Moderate CYP2D6 inhibitors: Sertraline, cimetidine, amiodarone, doxepin, ticlopidine, or haloperidol Duration of coadministration: <1, 1-2, 2-3, 3-4 and 4-5 years Statistics: Log rank test and Cox modeling CP
Methods CYP2D6 metabolism defined by *4 genotype and medication history Extensive CYP2D6 metabolism Wt/Wt, no inhibitor Decreased CYP26 metabolism Wt/*4 *4/*4 Any genotype and co-administration (yes/no) of a moderate or potent CYP2D6 inhibitor
Patient Characteristics Metabolizer status known n=180 Median age (range)68 (42-87) ER status (%)100 Tumor size (cm) <3 (%) 78 3 (%) 22 Positive nodes 0 (%) (%) (%) 7 10 (%) 4 Tumor grade 1 (%) 24 2 (%) 54 3 (%) 15 Unknown (%) 7 CP Goetz et al. Breast Cancer Res Treat (In press)
Results CP CYP2D6 metabolism determined in 180 pts (medication history 225 pts) Inhibitor status Potent inhibitors (n=3) Moderate inhibitors (n=10) Median duration of use 2-3 years Goetz et al. Breast Cancer Res Treat (In press)
Time to Breast Recurrence CP % Years after randomization P=0.015 Extensive Decreased n=115 n=65 Goetz et al. Breast Cancer Res Treat (In press)
Relapse-Free Survival CP % Years after randomization P=0.007 Extensive Decreased n=115 n=65 Goetz et al. Breast Cancer Res Treat (In press)
Overall Survival CP % Years after randomization P=0.082 Extensive Decreased n=115 n=65 Goetz et al. Breast Cancer Res Treat (In press)
Outcomes by Metabolizer Status Multivariate Analysis* Hazard ratio (relative to Outcomeextensive metabolizers)P value Time to breast recurrence1.91 ( )0.034 Relapse-free survival1.74 ( )0.017 Overall survival1.35 ( )0.223 CP *Adjusted for size, grade and nodal status, ER, PR, HER-2 Goetz et al. Breast Cancer Res Treat (In press)
Inhibition of CYP2D6 Affects Endoxifen Concentrations CP Jin Y et al: J Natl Cancer Inst 97:30, 2005 Wt/Wt, no inhibitor VenlafaxineSertralineParoxetine*4/*4, no inhibitor Plasma Endoxifen (nM)
CYP2D6 Metabolism by Genotype and Inhibitor Decreased CYP2D6 Metabolism Intermediate metabolizers: n=40 Wt/*4 and no inhibitor (n=32) Wt/Wt and moderate inhibitor (n=8) Poor metabolizers: n=16 4/*4 (n=13) Any genotype and potent inhibitor (n=3) Unknown: n=9 Wt/*4 without med history (n=7) Unknown genotype and mod inhibitor (n=2) Goetz et al. Breast Cancer Res Treat (In press)
Time to Breast Recurrence CP % Years after randomization Log Rank P=0.019 EM IM PM n=115 n=40 n=16 Goetz et al. Breast Cancer Res Treat (In press)
Relapse-Free Survival CP % Years after randomization 2-year RFS EM 98% IM 92% PM 68% Log Rank P=0.009 EM IM PM n=115 n=40 n=16 Goetz et al. Breast Cancer Res Treat (In press)
Overall Survival CP % Years after randomization Log Rank P=0.145 EM IM PM n=115 n=40 n=16 Goetz et al. Breast Cancer Res Treat (In press)
Outcomes by Metabolizer Status Univariate Analysis Hazard ratio (relative to Outcomeextensive metabolizers)P value Time to breast recurrence PM3.20 ( )0.007 IM1.49 ( ) Relapse-free survival PM2.69 ( )0.005 IM1.63 ( )0.075 Overall survival PM2.00 ( )0.077 IM1.40 ( )0.240 CP Goetz et al. Breast Cancer Res Treat (In press)
ATAC: Smoothed Hazard Rates for Recurrence Hormone Receptor + patients Follow-up time (years) Anastrozole Tamoxifen 0 Annual hazard rates (%) Howell, et al San Antonio Breast Cancer Symposium
Hazard Rates for RFS by CYP2D6 Metabolizer Status (n=180) CP Hazard rates Years after randomization Decreased Extensive Goetz et al. Breast Cancer Res Treat (In press)
Conclusion In this trial, CYP2D6 metabolism was an independent predictor of clinical outcome in postmenopausal women with ER positive early breast cancer The effect of impaired metabolism was most marked in poor metabolizers Consistent with clinical data that tamoxifen activation to endoxifen is dependent upon CYP2D6 CP
Conclusion These data suggest that determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and moderate/potent CYPY2D6 inhibitors should not be co-administered with tamoxifen CP
Acknowledgments Mayo Clinic Cancer Center North Central Cancer Treatment Group Pharmacogenetics Research Network COBRA : The Consortium for Breast Cancer Pharmacogenomics: Indiana University School of Medicine University of Michigan Johns Hopkins University Mayo Clinic Baylor College of Medicine Mayo Clinic Breast Cancer SPORE
CYP2D6 Individualized Adjuvant Hormonal Study Postmenopausal women ER positive breast cancer UM: Ultra-rapid Metabolizer EM: Extensive Metabolizer IM: Intermediate Metabolizer PM: Poor Metabolizer Standard of care (AI for 5 years) RANDOMIZERANDOMIZERANDOMIZERANDOMIZE EM, UM Tam (2.5 years) followed by AI (2.5 years) (n=1950) AI (5 years total) (n=1950) CYP2D6 Genotyping IM, PM CYP2D6 IM, and PM: heterozygous or homozygous for *3, *4, *5, *6, *7, *8, *11, *12