Genetic Study of CYP2D6 Enzyme and Therapeutic Drug Monitoring of Tamoxifen

NCT03582865 | Unknown

• 1 other identifier: Genetic study and TDM
• Study Type: observational
• Target: 100
• Locations: 0 countries
• Sites: N/A

Brief Summary

Aim of work:

1. 1.To estimate the frequency of Cyp2D6\*1 and \*4 alleles in Egyptian patients maintained on tamoxifen (20 mg/day) for management of ER +ve breast cancer.
2. 2.To measure levels of tamoxifen, 4-hydroxy tamoxifen, N-desmethyl-tamoxifen and 4- hydroxyl-N-desmethyl-tamoxifen (endoxifen) in the serum of these patients.
3. 3.To correlate between the levels of tamoxifen/active metabolite enoxifen ratio and CYP2D6\*1,\*4 genotyping.
4. 4.To investigate which is more valuable investigatory tool for prediction of the clinical outcome (response and/or toxicity) in these patients; either the measurements related to pharmacokinetics: tamoxifen/endoxifen levels or the pharmacogenetic analysis of CYP2D6 \*1,\*4.

Conditions

Breast Cancer

Keywords

Breast cancer; Genotyping; Tamoxifen

Outcome Measures

Primary Outcomes (1)

• Estimate the frequency of Cyp2D6*1 and *4 alleles in Egyptian patients maintained on tamoxifen (20 mg/day) for management of ER +ve breast cancer.

  The CYP2D6 genotypes will be determined using the TaqMan Allelic Discrimination Assay.

  6 months

Secondary Outcomes (1)

• measuring levels of tamoxifen, 4-hydroxy tamoxifen, N-desmethyl-tamoxifen and 4- hydroxyl-N-desmethyl-tamoxifen (endoxifen) in the serum ofbreast cancer patients.

  2 months

Study Arms (3)

responding

patients who received Tamoxifen 20 mg daily for at least 3 years with good response (no relapse) to tamoxifen. Both genotyping assessment and TDM of tamoxifen and its metabolites will be performed and correlated with the records. Follow up for these patients for further assessment of tamoxifen effectiveness will be carried out for 1- 2 years.

Drug: Tamoxifen 20 mg

relapse

patients who received Tamoxifen 20 mg daily for at least 3 years who were good responder to the drug but then the response has been diminished (relapse) and they have been shifted to another therapy. They will be exposed to genotyping study of CYP 2D6 to recognize the phenotyping style of that patient that may explain diminishing of response to tamoxifen therapy.

Drug: Tamoxifen 20 mg

tamoxifen resistant

patients who received Tamoxifen 20 mg daily for not more than 1 year with poor response to tamoxifen (early relapse) and clinically will be shifted to use another medication as they were diagnosed as tamoxifen resistant. Like the second group, they will be exposed to genotyping study of CYP2D6 with the same concept.

Drug: Tamoxifen 20 mg

Interventions

Tamoxifen 20 mg DRUG

Tamoxifen 20 mg is a selective estrogen receptor modulator

Also known as: Genetic

relapse; responding; tamoxifen resistant

Eligibility Criteria

• Age: 20 Years - 50 Years
• Sex: female
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Premenopausal women suffering from breast cancer

You may qualify if:

• Premenopausal patients will be included in this study, with hormone receptor positive tumors.
• The hormone receptor positive tumor is diagnosed by microscopic examination if ≥ 10% of the cells are positive for estrogen by immunohistochemistry analysis.
• All patients with normal hepatic and renal function, aspartate aminotransferase and alanine aminotransferase (≤2 upper normal limit) and serum creatinine (≤1.2 mg/dl).

You may not qualify if:

• Patients treated with other hormonal therapy, radiation or chemotherapy will be excluded from the study.
• Pregnant or breast feeding women will be excluded from the study.
• Patients who are taking drugs that are known to inhibit CYP2D6 activity as SSRIs will be excluded from the study.

Sponsors & Collaborators

• Assiut University: lead

Related Publications (20)

• Johnston SR. New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res. 2010 Apr 1;16(7):1979-87. doi: 10.1158/1078-0432.CCR-09-1823. Epub 2010 Mar 23.

  PMID: 20332324 BACKGROUND

• Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Medeiros Alencar VH, Badran A, Bonfill X, Bradbury J, Clarke M, Collins R, Davis SR, Delmestri A, Forbes JF, Haddad P, Hou MF, Inbar M, Khaled H, Kielanowska J, Kwan WH, Mathew BS, Mittra I, Muller B, Nicolucci A, Peralta O, Pernas F, Petruzelka L, Pienkowski T, Radhika R, Rajan B, Rubach MT, Tort S, Urrutia G, Valentini M, Wang Y, Peto R; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013 Mar 9;381(9869):805-16. doi: 10.1016/S0140-6736(12)61963-1.

  PMID: 23219286 BACKGROUND

• Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, Buyse M, Baum M, Buzdar A, Colleoni M, Coombes C, Snowdon C, Gnant M, Jakesz R, Kaufmann M, Boccardo F, Godwin J, Davies C, Peto R. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 2010 Jan 20;28(3):509-18. doi: 10.1200/JCO.2009.23.1274. Epub 2009 Nov 30.

  PMID: 19949017 BACKGROUND

• Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, Senn HJ; Panel members. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013 Sep;24(9):2206-23. doi: 10.1093/annonc/mdt303. Epub 2013 Aug 4.

  PMID: 23917950 BACKGROUND

• Lu WJ, Xu C, Pei Z, Mayhoub AS, Cushman M, Flockhart DA. The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents. Breast Cancer Res Treat. 2012 May;133(1):99-109. doi: 10.1007/s10549-011-1699-4. Epub 2011 Aug 4.

  PMID: 21814747 BACKGROUND

• Klein DJ, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE. PharmGKB summary: tamoxifen pathway, pharmacokinetics. Pharmacogenet Genomics. 2013 Nov;23(11):643-7. doi: 10.1097/FPC.0b013e3283656bc1. No abstract available.

  PMID: 23962908 BACKGROUND

• Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z, Flockhart DA, Skaar TC. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004 May;85(2):151-9. doi: 10.1023/B:BREA.0000025406.31193.e8.

  PMID: 15111773 BACKGROUND

• Murdter TE, Schroth W, Bacchus-Gerybadze L, Winter S, Heinkele G, Simon W, Fasching PA, Fehm T; German Tamoxifen and AI Clinicians Group; Eichelbaum M, Schwab M, Brauch H. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma. Clin Pharmacol Ther. 2011 May;89(5):708-17. doi: 10.1038/clpt.2011.27. Epub 2011 Mar 30.

  PMID: 21451508 BACKGROUND

• Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008 Feb;83(2):234-42. doi: 10.1038/sj.clpt.6100406. Epub 2007 Oct 31.

  PMID: 17971818 BACKGROUND

• Borges S, Desta Z, Jin Y, Faouzi A, Robarge JD, Philips S, Nguyen A, Stearns V, Hayes D, Rae JM, Skaar TC, Flockhart DA, Li L. Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients. J Clin Pharmacol. 2010 Apr;50(4):450-8. doi: 10.1177/0091270009359182. Epub 2010 Jan 15.

  PMID: 20081063 BACKGROUND

• Saladores P, Murdter T, Eccles D, Chowbay B, Zgheib NK, Winter S, Ganchev B, Eccles B, Gerty S, Tfayli A, Lim JS, Yap YS, Ng RC, Wong NS, Dent R, Habbal MZ, Schaeffeler E, Eichelbaum M, Schroth W, Schwab M, Brauch H. Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. Pharmacogenomics J. 2015 Feb;15(1):84-94. doi: 10.1038/tpj.2014.34. Epub 2014 Aug 5.

  PMID: 25091503 BACKGROUND

• Hertz DL, Snavely AC, McLeod HL, Walko CM, Ibrahim JG, Anderson S, Weck KE, Magrinat G, Olajide O, Moore S, Raab R, Carrizosa DR, Corso S, Schwartz G, Peppercorn JM, Evans JP, Jones DR, Desta Z, Flockhart DA, Carey LA, Irvin WJ Jr. In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles. Br J Clin Pharmacol. 2015 Nov;80(5):1122-30. doi: 10.1111/bcp.12665. Epub 2015 Aug 2.

  PMID: 25907378 BACKGROUND

• de Vries Schultink AH, Zwart W, Linn SC, Beijnen JH, Huitema AD. Effects of Pharmacogenetics on the Pharmacokinetics and Pharmacodynamics of Tamoxifen. Clin Pharmacokinet. 2015 Aug;54(8):797-810. doi: 10.1007/s40262-015-0273-3.

  PMID: 25940823 BACKGROUND

• Goetz MP, Suman VJ, Hoskin TL, Gnant M, Filipits M, Safgren SL, Kuffel M, Jakesz R, Rudas M, Greil R, Dietze O, Lang A, Offner F, Reynolds CA, Weinshilboum RM, Ames MM, Ingle JN. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res. 2013 Jan 15;19(2):500-7. doi: 10.1158/1078-0432.CCR-12-2153. Epub 2012 Dec 4.

  PMID: 23213055 BACKGROUND

• Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P, Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Bolander J, Strick R, Beckmann MW, Koelbl H, Weinshilboum RM, Ingle JN, Eichelbaum M, Schwab M, Brauch H. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009 Oct 7;302(13):1429-36. doi: 10.1001/jama.2009.1420.

  PMID: 19809024 BACKGROUND

• Nakamura Y, Ratain MJ, Cox NJ, McLeod HL, Kroetz DL, Flockhart DA. Re: CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial. J Natl Cancer Inst. 2012 Aug 22;104(16):1264; author reply 1266-8. doi: 10.1093/jnci/djs304. Epub 2012 Jul 31. No abstract available.

  PMID: 22851270 BACKGROUND

• Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, Kalyana-Sundaram S, Wang R, Ning Y, Hodges L, Gursky A, Siddiqui J, Tomlins SA, Roychowdhury S, Pienta KJ, Kim SY, Roberts JS, Rae JM, Van Poznak CH, Hayes DF, Chugh R, Kunju LP, Talpaz M, Schott AF, Chinnaiyan AM. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013 Dec;45(12):1446-51. doi: 10.1038/ng.2823. Epub 2013 Nov 3.

  PMID: 24185510 BACKGROUND

• Li S, Shen D, Shao J, Crowder R, Liu W, Prat A, He X, Liu S, Hoog J, Lu C, Ding L, Griffith OL, Miller C, Larson D, Fulton RS, Harrison M, Mooney T, McMichael JF, Luo J, Tao Y, Goncalves R, Schlosberg C, Hiken JF, Saied L, Sanchez C, Giuntoli T, Bumb C, Cooper C, Kitchens RT, Lin A, Phommaly C, Davies SR, Zhang J, Kavuri MS, McEachern D, Dong YY, Ma C, Pluard T, Naughton M, Bose R, Suresh R, McDowell R, Michel L, Aft R, Gillanders W, DeSchryver K, Wilson RK, Wang S, Mills GB, Gonzalez-Angulo A, Edwards JR, Maher C, Perou CM, Mardis ER, Ellis MJ. Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep. 2013 Sep 26;4(6):1116-30. doi: 10.1016/j.celrep.2013.08.022. Epub 2013 Sep 19.

  PMID: 24055055 BACKGROUND

• Lien EA, Ueland PM, Lonning PE. Re: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2004 Jun 2;96(11):884; author reply 884-5. doi: 10.1093/jnci/djh160. No abstract available.

  PMID: 15173277 BACKGROUND

• Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol. 2005 May;55(5):471-8. doi: 10.1007/s00280-004-0926-7. Epub 2005 Feb 1.

  PMID: 15685451 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Tamoxifen

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Amira Taha

  Assiut University

  PRINCIPAL INVESTIGATOR

• Ehab Eldesoky

  Assiut University

  STUDY DIRECTOR

• Mohammad Hareedy

  Assiut University

  STUDY DIRECTOR

Central Study Contacts

Amira Taha

CONTACT

+201003606486; dr_amira.fawzy88@hotmail.com

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Lecturer

Study Record Dates

• First Submitted: June 28, 2018
• First Posted: July 11, 2018
• Study Start: September 1, 2019
• Primary Completion: September 1, 2020
• Study Completion: December 1, 2020
• Last Updated: July 8, 2019

Record last verified: 2018-07