Breast CancerNCT03582865
Genetic Study of CYP2D6 Enzyme and Therapeutic Drug Monitoring of Tamoxifen
An observational study of Breast Cancer, run by Assiut University.
Trial summary
Aim of work: 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. To measure levels of tamoxifen, 4-hydroxy tamoxifen, N-desmethyl-tamoxifen and 4- hydroxyl-N-desmethyl-tamoxifen (endoxifen) in the serum of these… Read more about this study
- Who is it for?
- Ages 20 to 50 years, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Tamoxifen 20 mg
- How many people
- 100 participants
- Where
- No sites listed yet
- Study dates
- 1 Sep 2019to Dec 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 50 years
- Women only
- Adult
Study population: Premenopausal women suffering from breast cancer
Who may be able to join
- 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).
Who cannot join
- 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.
Trial locations and contacts
No sites are listed yet.
About this study
Official title: Genetic Study of CYP2D6 Enzyme and Therapeutic Drug Monitoring of Tamoxifen in Premenopausal Women With Breast Cancer
Aim of work:
- 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.
- To measure levels of tamoxifen, 4-hydroxy tamoxifen, N-desmethyl-tamoxifen and 4- hydroxyl-N-desmethyl-tamoxifen (endoxifen) in the serum of these patients.
- To correlate between the levels of tamoxifen/active metabolite enoxifen ratio and CYP2D6*1,*4 genotyping.
- 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.
Read the detailed description
Breast cancer is considered to be the most common cancer among women worldwide. The majority of breast cancer cases (almost 80%) are classified as hormone-dependent cancer, since estrogen, acting via estrogen receptor alpha (ER-α) or estrogen receptor beta (ER-β), is the major inducer of the development and growth of the tumor. These are also called ER-positive breast cancers. The remaining cases are not induced by estrogen and are classified as hormone-independent, or ER-negative, cancers. Since the growth of hormone-dependent cancer cells can be down-regulated by the oppositely active hormones, several endocrine therapies that limit the actions of estrogen (through blocking its production or its receptors) have been developed over the past years. These endocrine therapies have played an important part in treating and improving the outcomes of women with all stages of the disease . Selective estrogen receptor modulators (SERMs) have also been studied for their anti-cancer activity.
Selective estrogen receptor modulators (SERMs) are a class of drugs that act on the estrogen receptor (ER); a characteristic that distinguishes these substances from pure ER agonists and antagonists as their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues .
Tamoxifen, which is a SERM, is important for the treatment and prevention of estrogen receptor (ER) positive breast cancer commonly in premenopausal women. It has been shown to decrease disease recurrence and mortality rates by as much as 50% and 30% respectively. It has been also used as a prophylactic treatment for patients who are at high risk of developing breast cancer. Post-menopausal breast cancer patients are commonly treated nowadays with aromatase inhibitors (AIs) for 5 years, alone or combined with tamoxifen for a 3-5 year period. Tamoxifen monotherapy in postmenopausal women with breast cancer may be used for 10 years if the side effects from AIs are too bothersome .
Besides acting as SERMs, it has recently been found that some of tamoxifen's metabolites (as norendoxifen) also act as aromatase inhibitors in vitro. Aromatase converts steroids (e.g., testosterone to estradiol), the inhibition of which severely decreases the amount of available estrogen in the body .
The most common side effects of Tamoxifen:
- Hot flashes, the most common side effect of tamoxifen, affect up to 80% of women.
- Increased risk of endometrial hyperplasia and polyps
- Increased risk for cataract.
- Increased risk for thromboembolic events as well as clinical depression .
Pharmacokinetics of tamoxifen and its clinical implications:
Tamoxifen is a prodrug that is metabolized by several cytochrome P450 enzymes. It is a relatively weak antiestrogen in comparison to its active metabolites, particularly endoxifen. Two parallel pathways bioactivate tamoxifen to endoxifen (4-OH-N-desmethyltamoxifen) through several overlapping cytochrome P450 (CYP) enzymes; primarily CYP3A4/5 and CYP2D6.
For many years, 4-hydroxy-tamoxifen has believed to be primarily responsible for the clinical activity; however, the CYP2D6 metabolites 4-hydroxy-tamoxifen and endoxifen (4-OH-N-desmethyl-tamoxifen) have equal affinity for the estrogen receptor. Because serum concentrations of endoxifen are 6 to 12 times higher than 4-hydroxy-tamoxifen in patients receiving long-term tamoxifen therapy, many think endoxifen is the most significant tamoxifen metabolite.
The rate limiting step in tamoxifen metabolism is catalyzed by the highly polymorphic CYP2D6 enzyme so that CYP2D6 genotype can be translated into predicted metabolic activity phenotypes: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), ultrarapid metabolizer (UM), which are strongly predictive of endoxifen concentration during tamoxifen treatment.
There is substantial variation in CYP2D6 genotypes among different populations. CYP2D6*1 is the wild-type allele and is associated with normal enzyme activity and the normal "extensive metabolizer" phenotype. The CYP2D6 alleles *2, *33, and *35 are also considered to have near-normal activity. Other alleles include variants that produce a non-functioning enzyme (e.g., *3, *4, *5, and *6) or an enzyme with reduced activity (e.g., *10, *17, and *41). There are large inter-ethnic differences in the frequency of these alleles, with *3, *4, *5, *6, and *41 being more common in the Caucasian population, *17 more common in Africans, and *10 more common in Asians. Also it was found that *1 and *4 alleles are more common in Egyptians.
Patients with low-activity CYP2D6 phenotypes have substantially lower endoxifen steady-state concentrations . It is unclear whether patients with genotypes that confer low CYP2D6 activity have inferior efficacy from tamoxifen treatment, but if so, preemptive genotyping to guide tamoxifen dose selection could be a viable strategy to improve treatment effectiveness.
Despite the proven efficacy of tamoxifen, some women experience cancer recurrence during or after treatment. Therapeutic failure may be caused by tumor resistance to antiestrogen therapy or inadequate bioactivation of tamoxifen to its active metabolite, endoxifen.
Some studies have reported that patients with low endoxifen concentrations (below 5.9 ng/ml) have increased the risk of inferior tamoxifen efficacy with consequent cancer recurrence compared with its concentration in intermediate and rapid or ultra-rapid metabolizers taking the same dose. This can open the way for application of therapeutic drug monitoring of tamoxifen and its metabolite endoxifen for possible dose escalation especially a fixed dose of the drug is usually used which is 20 mg/day.
The issue of relying on genotyping profile of CYP2D6 and its variants or use of TDM of tamoxifen and its metabolite endoxifen or the combination of both parameters to correlate with clinical response, adverse effect and dose modification of tamoxifen is still under investigation.
- Conditions
- Breast Cancer
- Being tested
- Tamoxifen 20 mg
- Keywords
- Breast cancer, Genotyping, Tamoxifen
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tamoxifen 20 mgDrug
Also called Genetic
Tamoxifen 20 mg is a selective estrogen receptor modulator
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: Tamoxifen 20 mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Plasma concentrations of tamoxifen, 4-hydroxy-tamoxifen (4-OH-tam), N-desmethyl-tamoxifen (N-DM-tam) and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen) will be measured using sensitive HPLC-PDA assay method.
Measured: 2 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jul 2018
- Study start1 Sep 2019 (estimated)
- Primary completionSep 2020 (estimated)
- Study completionDec 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (20)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by Assiut UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assiut University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Amira Fawzy Taha, Assiut University
- Investigators
- Amira Taha, Principal investigator, Assiut UniversityEhab Eldesoky, Study director, Assiut UniversityMohammad Hareedy, Study director, Assiut University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03582865
- Sponsor's protocol ID
- Genetic study and TDM
- Status last verified
- Jul 2018
- First submitted
- 28 Jun 2018
- Last updated
- 8 Jul 2019
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 20332324Davies 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.
PubMed 23219286Dowsett 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.
PubMed 19949017Goldhirsch 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.
PubMed 23917950Lu 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.
PubMed 21814747Klein 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.
PubMed 23962908Johnson 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.
PubMed 15111773Murdter 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.
PubMed 21451508Gaedigk 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.
PubMed 17971818Borges 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.
PubMed 20081063Saladores 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.
PubMed 25091503Hertz 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.
PubMed 25907378de 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.
PubMed 25940823Goetz 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.
PubMed 23213055Schroth 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.
PubMed 19809024
Study at a glance
From the registry record, last updated by the sponsor on 8 Jul 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Genetic Study of CYP2D6 Enzyme and Therapeutic Drug Monitoring of Tamoxifen in Premenopausal Women With Breast Cancer
- ClinicalTrials.gov ID
- NCT03582865
- Acronym / sponsor ID
- Genetic study and TDM
- Conditions
- Breast Cancer
- Keywords
- Breast cancer, Genotyping, Tamoxifen
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- Assiut UniversityUniversity, hospital or other
- Study start
- 1 Sep 2019 (estimated)
- Primary completion
- Sep 2020 (estimated)
- Study completion
- Dec 2020 (estimated)
- First posted
- 11 Jul 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Aim of work:
- 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.
- To measure levels of tamoxifen, 4-hydroxy tamoxifen, N-desmethyl-tamoxifen and 4- hydroxyl-N-desmethyl-tamoxifen (endoxifen) in the serum of these patients.
- To correlate between the levels of tamoxifen/active metabolite enoxifen ratio and CYP2D6*1,*4 genotyping.
- 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.
Detailed description
Breast cancer is considered to be the most common cancer among women worldwide. The majority of breast cancer cases (almost 80%) are classified as hormone-dependent cancer, since estrogen, acting via estrogen receptor alpha (ER-α) or estrogen receptor beta (ER-β), is the major inducer of the development and growth of the tumor. These are also called ER-positive breast cancers. The remaining cases are not induced by estrogen and are classified as hormone-independent, or ER-negative, cancers. Since the growth of hormone-dependent cancer cells can be down-regulated by the oppositely active hormones, several endocrine therapies that limit the actions of estrogen (through blocking its production or its receptors) have been developed over the past years. These endocrine therapies have played an important part in treating and improving the outcomes of women with all stages of the disease . Selective estrogen receptor modulators (SERMs) have also been studied for their anti-cancer activity.
Selective estrogen receptor modulators (SERMs) are a class of drugs that act on the estrogen receptor (ER); a characteristic that distinguishes these substances from pure ER agonists and antagonists as their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues .
Tamoxifen, which is a SERM, is important for the treatment and prevention of estrogen receptor (ER) positive breast cancer commonly in premenopausal women. It has been shown to decrease disease recurrence and mortality rates by as much as 50% and 30% respectively. It has been also used as a prophylactic treatment for patients who are at high risk of developing breast cancer. Post-menopausal breast cancer patients are commonly treated nowadays with aromatase inhibitors (AIs) for 5 years, alone or combined with tamoxifen for a 3-5 year period. Tamoxifen monotherapy in postmenopausal women with breast cancer may be used for 10 years if the side effects from AIs are too bothersome .
Besides acting as SERMs, it has recently been found that some of tamoxifen's metabolites (as norendoxifen) also act as aromatase inhibitors in vitro. Aromatase converts steroids (e.g., testosterone to estradiol), the inhibition of which severely decreases the amount of available estrogen in the body .
The most common side effects of Tamoxifen:
- Hot flashes, the most common side effect of tamoxifen, affect up to 80% of women.
- Increased risk of endometrial hyperplasia and polyps
- Increased risk for cataract.
- Increased risk for thromboembolic events as well as clinical depression .
Pharmacokinetics of tamoxifen and its clinical implications:
Tamoxifen is a prodrug that is metabolized by several cytochrome P450 enzymes. It is a relatively weak antiestrogen in comparison to its active metabolites, particularly endoxifen. Two parallel pathways bioactivate tamoxifen to endoxifen (4-OH-N-desmethyltamoxifen) through several overlapping cytochrome P450 (CYP) enzymes; primarily CYP3A4/5 and CYP2D6.
For many years, 4-hydroxy-tamoxifen has believed to be primarily responsible for the clinical activity; however, the CYP2D6 metabolites 4-hydroxy-tamoxifen and endoxifen (4-OH-N-desmethyl-tamoxifen) have equal affinity for the estrogen receptor. Because serum concentrations of endoxifen are 6 to 12 times higher than 4-hydroxy-tamoxifen in patients receiving long-term tamoxifen therapy, many think endoxifen is the most significant tamoxifen metabolite.
The rate limiting step in tamoxifen metabolism is catalyzed by the highly polymorphic CYP2D6 enzyme so that CYP2D6 genotype can be translated into predicted metabolic activity phenotypes: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), ultrarapid metabolizer (UM), which are strongly predictive of endoxifen concentration during tamoxifen treatment.
There is substantial variation in CYP2D6 genotypes among different populations. CYP2D6*1 is the wild-type allele and is associated with normal enzyme activity and the normal "extensive metabolizer" phenotype. The CYP2D6 alleles *2, *33, and *35 are also considered to have near-normal activity. Other alleles include variants that produce a non-functioning enzyme (e.g., *3, *4, *5, and *6) or an enzyme with reduced activity (e.g., *10, *17, and *41). There are large inter-ethnic differences in the frequency of these alleles, with *3, *4, *5, *6, and *41 being more common in the Caucasian population, *17 more common in Africans, and *10 more common in Asians. Also it was found that *1 and *4 alleles are more common in Egyptians.
Patients with low-activity CYP2D6 phenotypes have substantially lower endoxifen steady-state concentrations . It is unclear whether patients with genotypes that confer low CYP2D6 activity have inferior efficacy from tamoxifen treatment, but if so, preemptive genotyping to guide tamoxifen dose selection could be a viable strategy to improve treatment effectiveness.
Despite the proven efficacy of tamoxifen, some women experience cancer recurrence during or after treatment. Therapeutic failure may be caused by tumor resistance to antiestrogen therapy or inadequate bioactivation of tamoxifen to its active metabolite, endoxifen.
Some studies have reported that patients with low endoxifen concentrations (below 5.9 ng/ml) have increased the risk of inferior tamoxifen efficacy with consequent cancer recurrence compared with its concentration in intermediate and rapid or ultra-rapid metabolizers taking the same dose. This can open the way for application of therapeutic drug monitoring of tamoxifen and its metabolite endoxifen for possible dose escalation especially a fixed dose of the drug is usually used which is 20 mg/day.
The issue of relying on genotyping profile of CYP2D6 and its variants or use of TDM of tamoxifen and its metabolite endoxifen or the combination of both parameters to correlate with clinical response, adverse effect and dose modification of tamoxifen is still under investigation.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| responding | – | Drug: Tamoxifen 20 mgpatients 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. |
| relapse | – | Drug: Tamoxifen 20 mgpatients 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. |
| tamoxifen resistant | – | Drug: Tamoxifen 20 mgpatients 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. |
Who may qualify
- Ages
- 20 to 50 years
- Sex
- Female only
- Age groups
- Adult
- Study population
- Premenopausal women suffering from breast cancer
Key inclusion criteria (3 listed)
- 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).
Key exclusion criteria (3 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tamoxifen 20 mgAlso: GeneticTamoxifen 20 mg is a selective estrogen receptor modulator | Drug | relapse, responding, tamoxifen resistant |
Primary outcome
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.
Time frame: 6 months
The CYP2D6 genotypes will be determined using the TaqMan Allelic Discrimination Assay.
1 secondary outcome
measuring levels of tamoxifen, 4-hydroxy tamoxifen, N-desmethyl-tamoxifen and 4- hydroxyl-N-desmethyl-tamoxifen (endoxifen) in the serum ofbreast cancer patients.
Time frame: 2 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Jul 2019.
- Background: PubMed 20332324Johnston 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.
- Background: PubMed 23219286Davies 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.
- Background: PubMed 19949017Dowsett 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.
- Background: PubMed 23917950Goldhirsch 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Amira Taha principal investigator
Assiut University
Ehab Eldesoky study director
Assiut University
Mohammad Hareedy study director
Assiut University
Questions about this trial
What is this clinical trial studying?
An observational study of Breast Cancer, run by Assiut University.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 8 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Amira Taha (+201003606486, dr_amira.fawzy88@hotmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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. (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03582865, which also lists 20 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jul 2019.