Tamoxifen And CYP2D6:  Using Pharmacogenetics to discover a new drug
Upcoming SlideShare
Loading in...5
×

Like this? Share it with your network

Share

Tamoxifen And CYP2D6: Using Pharmacogenetics to discover a new drug

  • 3,308 views
Uploaded on

Dr. Matthew Goetz, assistant professor of oncology and pharmacology at the Mayo Clinic, shared his pharmacogenomic research findings related to risks and occurrence of breast cancer. He explained......

Dr. Matthew Goetz, assistant professor of oncology and pharmacology at the Mayo Clinic, shared his pharmacogenomic research findings related to risks and occurrence of breast cancer. He explained that in order to truly personalize medicine, you must account for all possible theories and variables. Goetz continued to say that although many believe pharmacology to be boring, it is a key component of the future model of care. Some may say, so this drug doesn’t work–why not just try another drug? It’s much more complicated than that.

Dr. Goetz touched on the variety of cases in his study in breast cancer patients, some with strange and perplexing results. When giving the same drug to multiple patients, each yielded a variety of different results. Some patients had successful reduction in tumor size, while others resulted in no change and some even experienced tumor growth as a result of the drug. Personalized health care is the answer to this, for lack of a better term, ’shot-in-the-dark’ type of therapy. If physicians can understand each patient’s biology and genetic makeup individually, they can better apply treatments and medications. This would therefore reduce health care costs and enable patients to receive much more efficient treatments.

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
No Downloads

Views

Total Views
3,308
On Slideshare
2,958
From Embeds
350
Number of Embeds
4

Actions

Shares
Downloads
101
Comments
0
Likes
1

Embeds 350

http://phc.osumc.edu 328
http://www.slideshare.net 15
http://phcconference.wordpress.com 6
http://www.365dailyjournal.com 1

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide
  • CP1338099 Ingle, J JS 12-03-2008
  • CP1338099 Ingle, J JS 12-03-2008
  • turned out to be basically correct except that there are numerous Mutations although one is most frequent: *4 how do this mutations knock out the function?

Transcript

  • 1. Tamoxifen And CYP2D6: Using Pharmacogenetics to discover a new drug Matthew P. Goetz, MD Associate Professor of Oncology Mayo Clinic CP1229323-1 Ohio State University Center: Conference on Personalized Health Care
  • 2. Current Applications of Pharmacogenomics in Breast Cancer
    • Current state of adjuvant hormonal therapy
    • Pharmacogenetics: CYP2D6 and tamoxifen
    • Future directions: endoxifen as a novel hormonal therapy for breast cancer
  • 3. Breast Cancer 2008 (USA)
    • Invasive breast cancer: 178,480 new cases
    • Ductal carcinoma in situ: 62,030 cases
    • 2/3 are estrogen positive — candidates for hormonal therapy
    American Cancer Society: Breast Cancer Facts & Figures, 2007-2008
  • 4. Oxford Overview: 5 Years of Tamoxifen vs Not ER Positive vs ER Negative  5 Years Tamoxifen vs Not Recurrence ER+/ER Unknown Entry age  50  5 Years Tamoxifen vs Not Recurrence ER – Poor PR – Poor Recurrence Years Control 40.3%  5-yr TAM 23.5% 10-yr gain 15.0% (SE 1.1) Logrank 2P<0.00001 28.2 15.1  5-yr TAM 29.0% 21.3 20.8 Years Loss 1.9% (SE 1.5) Logrank 2P>0.1; NS Control 27.1% 50 40 30 20 10 0
  • 5. Cohort 1 Direct Comparison of Tamoxifen and an Aromatase Inhibitor (9,856 Patients) Ingle et al. SABC 2008
  • 6. Cohort 1  5 years of AI vs tamoxifen ER+ 10 0 20 30 40 50 %  SE 0 5 8 Years 15.3% AI 12.6% 9.6% 5-yr gain 2.9% (SE 0.7) 8-yr gain 3.9% (SE 1.0) Logrank 2P<0.00001 Years 0-1 2-4 ≥ 5 AI 1.69 (163/9647) 2.31 (261/11297) 2.33 (160/6879) Tamoxifen 2.46 (234/9510) 2.81 (307/10938) 2.78 (180/6478) Rate ratio, 0.67 SE 0.08 0.81 SE 0.08 0.83 SE 0.10 from (O-E)/V -38.4/96.6 -29.5/137.9 -15.7/83.0 Tamoxifen 19.2% Recurrence Ingle et al. SABC 2008
  • 7. Tamoxifen Metabolic Pathway (Humans) Jin Y et al: J Natl Cancer Inst 97:30, 2005 CP1230355-21 400-600 nM 5-10 nM 20-180 nM 200-300 nM Binding affinity relative to estradiol 1.00 for metabolites 4-OH TAM and endoxifen 0.01 for tamoxifen and N-desmethyl tamoxifen
  • 8. chromosome 22 CYP2D8 (pseudogene) CYP2D7 (pseudogene) CYP2D6 functional alleles *1, *2, *35 nonfunctional (null, *0) *3, *4, *5, *6, *7, *8, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38 .... CYP2D gene locus Molecular Basis of the CYP2D6 Polymorphism > 100 Genetic Variants duplicated alleles *1x2, *2x2, *35x2 low function alleles *9, *10, *17, *41, *59 q13.1
  • 9. CYP2D6 Genotype and Endoxifen 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)
  • 10. NCCTG 89-30-52 5 years of tamoxifen (20 mg qd) + 1 year of fluoxymesterone (10 mg po bid) 5 years of tamoxifen R A N D O M I Z A T I O N Postmenopausal women 5 years total therapy 541 women accrued Early ER + breast cancer
  • 11. Time to Recurrence According to CYP2D6 Metabolizer Status* in Women Receiving Adjuvant Tamoxifen % Years after randomization P<0.001 EM/EM, EM/IM EM/PM, IM/IM, PM/IM PM/PM (n=108) (n=65) (n=16) PM alleles: *3,*4,*6, IM alleles: *10, *17, *41 Potent CYP2D6 inhibitor = PM/PM Goetz et al J Clin Oncol. 2005;23(36):9312-8. Goetz M et al. Breast Cancer Res Treat 101:113-121, 2007
  • 12. ABCSG Trial 8 structure Randomize Switching period Sequencing period Jakesz R et al. Lancet 2005 Switch point Tamoxifen (2 years) Tamoxifen (3 years) Tamoxifen (2 years) Primary surgery Anastrozole (3 years)
  • 13. Event-free survival following adjuvant therapy switch (n = 2529) Time after switch (months) EFS (%) Anastrozole (A) Tamoxifen (T) HR 0.62 Events p-value 0.011 T 69 A 44 Therapy switch (2 years after surgery) 92.8% 88.9% 0 75 80 85 90 95 100 0 12 24 36 48 60 72
  • 14. ABCSG Trial 8 structure Randomize Switching period Sequencing period Jakesz R et al. Lancet 2005 Switch point Tamoxifen (2 years) Tamoxifen (3 years) Tamoxifen (2 years) Primary surgery Anastrozole (3 years)
  • 15. Arm A: Tamoxifen for 5 years (n=67 cases) Risk relative to extensive metabolizers P value CYP2D6 PM 3.83 (1.27-11.55) 0.017 CYP2D6 IM 0.87 (0.44-1.71) 0.689 CP1229323-18 Arm B: Tamoxifen to anastrozole (n=55 cases) Risk relative to extensive metabolizers P value CYP2D6 PM 1.02 (0.21-4.83) 0.985 CYP2D6 IM 0.81 (0.40-1.61) 0.538 CYP2D6 and Relative Risk of Breast Event Goetz et al. SABC 2008
  • 16. Arm A: Tamoxifen Years 3-5 (n=55 cases) Risk relative to extensive metabolizers P value CYP2D6 PM 2.81 (0.88-8.97) 0.081 CYP2D6 IM 0.75 (0.36-1.55) 0.431 CP1229323-18 Arm B: Anastrozole Years 3-5 (n=31 cases) CYP2D6 and Relative Risk of Breast Event Risk relative to extensive metabolizers P value CYP2D6 PM 0.71 (0.06-8.39) 0.782 CYP2D6 IM 0.57 (0.21-1.54) 0.269 Goetz et al. SABC 2008
  • 17. Mayo Clinic Rochester: Treatment of Postmenopausal, ER + Breast Cancer
    • Women should be informed
    • 1) data in support of CYP2D6 as key enzyme involved in the activation of tamoxifen
    • 2) Discontinuation of potent CYP2D6 inhibitors
    • 3) CYP2D6 genotyping: CYP2D6 PM do not receive tamoxifen
  • 18. New identified Mechanism of Action (Endoxifen)
    • Does endoxifen differ from Tamoxifen or 4-HT in its interaction with the estrogen receptor?
  • 19. Tamoxifen Mechanism of Action ER ER ER ER ER SRC D1 Coregulators Transcription Gene ERE Tamoxifen
  • 20. Endoxifen but not 4HT Results in Increased ER α Protein Turnover Wu et al: Cancer Res, 2009
  • 21. Tamoxifen Metabolic Pathway (Humans) Jin Y et al: J Natl Cancer Inst 97:30, 2005 CP1230355-21 400-600 nM 5-10 nM 20-180 nM 200-300 nM Binding affinity relative to estradiol 1.00 for metabolites 4-OH TAM and endoxifen 0.01 for tamoxifen and N-desmethyl tamoxifen
  • 22. High Concentrations of Endoxifen Suppress MCF-7 Cell Proliferation at Clinically Relevant Conditions Wu et al: Cancer Res, 2009 Relative fold change from vehicle Vehicle E2 E2+ com- bination (TAM+4HT +NDT) E2+ +20 nM endoxifen E2+ com- bination +40 nM endoxifen E2+ com- bination +100 nM endoxifen E2+ com- bination +1,000 nM endoxifen
  • 23. True Personalized Medicine: You need to account for all sources of variation: germ line, tumor, environmental
  • 24. Gene Expression Profiling van't Veer LJ et al: J Clin Oncol 23:1631, 2005 Unfixed sample of tumor tissue Surgical removal of tumor tissue Labeled tumor cDNA or cRNA Tumor RNA Comparative analysis of gene expression Molecular signature Poor prognosis Good prognosis Labeled control cDNA or cRNA DNA microarray
  • 25. Sorlie et al: Proc Natl Acad Sci USA 100:8418, 2003 Gene Expression Profiling Identifies Molecularly Distinct Subtypes A B C D E F
  • 26. Overexpression of HER-2 in Human Breast Cancer Cells Human breast cancer cells Transfect with HER2 gene DNA synthesis Cell growth rate Growth in soft agar Tumorigenicity Metastatic potential Transformed breast cancer cell Multiple copies of HER2, high expressor Single copy of HER2, low expressor
  • 27. Tamoxifen Stimulates the in Vivo Growth of HER-2 Expressing, ER+ Xenographs Shou J et al: J Natl Cancer Inst 96:926, 2004 -E2 TAM E2 P-MAPK THr 202 /Tyr 204 ) T-MAPK E2 TAM -E2 1 90 30 60 Tumor volume (mm 3 ) Days 1,400 1,000 200 0 600
  • 28. Tamoxifen, Endoxifen in MCF-7 HER2 expressing Breast Cancer Cells Goetz, Reinicke, Ames et al. unpublished
  • 29. Tamoxifen versus Endoxifen in HER-2 positive cells
    • Does CYP2D6 status (metabolic activation to endoxifen) impact the outcomes of patients with HER-2 positive breast cancer?
  • 30. NCCTG 89-30-52 5 years of tamoxifen (20 mg qd) + 1 year of fluoxymesterone (10 mg po bid) 5 years of tamoxifen R A N D O M I Z A T I O N Postmenopausal women 5 years total therapy 541 women accrued Early ER + breast cancer
  • 31. HER-2, CYP2D6 and Recurrence Free-Survival % Years from randomization EM/EM, EM/IM EM/PM, IM/IM, PM/IM, PM/PM P=0.006 n=9 n=10 CP1347559-1 PM alleles: *3, *4, *6 IM alleles: *10, *17, *41 Potent CYP2D6 inhibitor = PM/PM
  • 32. Pharmacology 101
    • Which tamoxifen molecule is occupying the estrogen receptor – tamoxifen, 4-hydroxy tamoxifen, endoxifen?
    • Who cares?
    • Pharmacology is boring – if the drug doesn’t work, just use a different drug
  • 33. Summary
    • The metabolic activation of tamoxifen precludes use for many women
    • In HER2 expressing breast cancer, tamoxifen activates but endoxifen potently inhibits tumor growth
    • Administration of endoxifen would bypass the genetic and concomitant drug effects on metabolism
  • 34. Murine Endoxifen Plasma Concentrations After PO Adminstration Endoxifen (nM) Minutes Reid, JR, Goetz, MP, Ames MM 4 mg/kg 200 mg/kg
  • 35.
    • How do we develop Endoxifen?
    • No intellectual property, thus no drug company interest
    • Can NCI facilitate the development of endoxifen?
    Next Steps
  • 36. Endoxifen Drug Development Timeline 2009 2010 2010-2011 2012-2015 Preclinical pharmacology and toxicology in mice NCI and Mayo complete preclinical Toxicology; clinical grade drug available Phase II studies begin Human phase I study begins
  • 37. Acknowledgments Matthew Ames Lab Joel Reid Katherine Reinicke Stephanie Safgren Mary Kuffel Sarah Buhrow James Ingle Vera J. Suman Tom Spelsberg lab John Hawse Xiaglin Wu Malayannan Subramaniam Richard Weinshilboum lab Ann Moyer Others Robert Jenkins Carol Reynolds
  • 38.
    • Mayo Clinic Cancer Center
    • North Central Cancer Treatment Group
    • ABCSG
    • 1R01CA133049-01 (Goetz)
    • Mayo Clinic Breast Cancer SPORE
    • K-12 (Paul Calabresi Scholar)
    • Pharmacogenetics Research Network (Dick Weinshilboum)