2.
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines): Breast Cancer Version 4.2017. February 7, 2018 [cited 19 March 2018]; Available from:
http://www.nccn.org/.
4. Goetz M.P., Sangkuhl K., Guchelaar H.J., Schwab M., et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. Clin Pharmacol Ther. 2018 May;103(5):770–777.
5. Royal Dutch Pharmacists Association (KNMP). Dutch Pharmacogenetics Working Group (DPWG). Pharmacogenetic Guidelines [Internet]. Netherlands. Tamoxifen – CYP2D6 [Cited May 2017]. Available from:
http://kennisbank.knmp.nl [Access is restricted to KNMP membership.]
3. Burstein H.J., Griggs J.J., Prestrud A.A., Temin S. American society of clinical oncology clinical practice guideline update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Oncol Pract. 2010 Sep;6(5):243–6.
This section contains excerpted
1
information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.
2018 Statement from the US Food and Drug Administration (FDA)
Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.
Please review the complete therapeutic recommendations that are located here:
(1).
2018 Statement from the National Comprehensive Cancer Network (NCCN)
The cytochrome P-450 (CYP450) enzyme, CYP2D6, is involved in the conversion of tamoxifen to endoxifen. Over 100 allelic variants of CYP2D6 have been reported in the literature. Individuals with wild-type CYP2D6 alleles are classified as extensive metabolizers of tamoxifen. Those with one or two variant alleles with either reduced or no activity are designated as intermediate metabolizers and poor metabolizers, respectively. A large retrospective study of 1325 patients found that time to disease recurrence was significantly shortened in poor metabolizers of tamoxifen. However, the Breast International Group (BIG) 1-98 trial reported on the outcome based on CYP2D6 genotype in a subset of postmenopausal patients with endocrine-responsive, early invasive breast cancer. The study found no correlation between CYP2D6 allelic status and disease outcome or between CYP2D6 allelic status and tamoxifen-related adverse effects. A genetic analysis of the ATAC trial found no association between CYP2D6 genotype and clinical outcomes. Given the limited and conflicting evidence at this time, the NCCN Breast Cancer Panel does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy. This recommendation is consistent with the ASCO Guidelines. When prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid potent and intermediate CYP2D6 inhibiting agents, particularly paroxetine and fluoxetine, if an appropriate alternative exists.
Please review the complete therapeutic recommendations that are located here:
(2).
2018 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC)
Table 3 summarizes the therapeutic recommendations for tamoxifen prescribing based on the CYP2D6 phenotype. Based on current evidence, CYP2D6 UMs and NMs are expected to achieve therapeutic endoxifen concentrations after administration of tamoxifen and should receive the recommended standard of care doses of tamoxifen. CYP2D6 PMs and IMs (including patients with an AS of 1.0, see Supplement) are expected to have lower endoxifen concentrations compared to NMs and have a higher risk of breast cancer recurrence, and worse event-free survival compared to NMs. For CYP2D6 PMs, a “strong” therapeutic recommendation was provided to recommend alternative hormonal therapy such as an aromatase inhibitor (AI) for postmenopausal women or AI along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype and based on knowledge that CYP2D6 PMs patients who switch from tamoxifen to anastrozole do not exhibit an increased risk of recurrence. Given that escalation of tamoxifen dose from 20–40 mg/day in CYP2D6 PM significantly increases endoxifen concentrations (but not to concentrations achieved in CYP2D6 NMs), the use of an AI (± ovarian function suppression) is recommended in this setting. Tamoxifen 40 mg/day can be considered for CYP2D6 PM if there are contraindications to AI use. There are no clinical data that toremifene, another selective estrogen receptor modulator that also undergoes bioactivation, should be substituted for tamoxifen based on CYP2D6 genotype.
For CYP2D6 IMs and CYP2D6*10/*10 or CYP2D6*10/decreased function allele, a “moderate” recommendation was made to consider use of an alternative hormonal therapy (i.e., aromatase inhibitor) for postmenopausal women or AI plus ovarian function suppression in premenopausal women is recommended. In CYP2D6 IMs, if AIs are contraindicated, consideration can be given to the use of a higher FDA-approved dose of tamoxifen (40 mg/day), which is known to result in significantly higher endoxifen concentrations without an increase in toxicity. Based on extrapolation from evidence in *10 individuals, a similar recommendation applies to individuals who carry other decreased function alleles resulting in an AS of 1.0 but with an “optional” recommendation, given the paucity of data for this group.
In general, prolonged overlap of tamoxifen with strong and moderate CYP2D6 inhibitors should be avoided in tamoxifen-treated patients, whereas weak inhibitors are also contraindicated in CYP2D6 IMs.
Please review the complete therapeutic recommendations that are located here:
(4)
2015 Summary of recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)
CYP2D6 IM: TAMOXIFEN
This gene variation reduces the conversion of tamoxifen to the active metabolite endoxifen. This can result in reduced effectiveness.
Recommendation:
- select an alternative or measure the endoxifen concentration and increase the dose if
necessary by a factor of 1.5-2
Aromatase inhibitors are a possible alternative for post-menopausal women.
2. if TAMOXIFEN is selected: avoid co-medication with CYP2D6 inhibitors such as paroxetine
and fluoxetine
CYP2D6 PM: TAMOXIFEN
This gene variation reduces the conversion of tamoxifen to the active metabolite endoxifen. This can result in reduced effectiveness.
Recommendation:
- select an alternative or increase the dose to 40 mg/day and monitor the endoxifen
concentration
Studies have demonstrated that PM can achieve an adequate endoxifen concentration when the dose is increased to 40-60 mg/day.
Aromatase inhibitors are a possible alternative for post-menopausal women.
CYP2D6 UM: TAMOXIFEN
No action is needed for this gene-drug interaction.
As a result of the genetic variation, the plasma concentration of the active metabolites 4- hydroxytamoxifen and endoxifen can increase. However, there is no evidence that this results in an increase in the side effects.
Background information
Mechanism: The main conversion route of tamoxifen is by CYP3A4/5 to the relatively inactive N-desmethyltamoxifen. This is converted by CYP2D6 to endoxifen (4-hydroxy-N-desmethyltamoxifen), which has an anti-oestrogenic effect that is 30-100x stronger than tamoxifen. Tamoxifen is further converted by CYP2D6 to the active metabolite 4-hydroxytamoxifen. This metabolite is as potent as endoxifen, but occurs at much lower concentrations. CYP3A4/5 converts 4-hydroxytamoxifen further to endoxifen.
Please review the complete therapeutic recommendations that are located here: (
5
).
2010 Excerpt from the American Society of Clinical Oncology (ASCO) guideline2
“Are There Specific Patient Populations That Derive Differing Degrees of Benefit from an AI Compared With Tamoxifen?”
Recommendation: Direct evidence from randomized trials does not identify a specific marker or clinical subset that predicted which adjuvant treatment strategy—tamoxifen, AI monotherapy, or sequential therapy—would maximally improve outcomes for a given patient. Among men with breast cancer, tamoxifen remains the standard adjuvant endocrine treatment. The Update Committee recommends against using CYP2D6 genotype to select adjuvant endocrine therapy. The Committee encouraged caution with concurrent use of CYP2D6 inhibitors (such as bupropion, paroxetine, fluoxetine; see Table 11 in the full guideline for a complete list of inhibitors) and tamoxifen because of the known drug-drug interactions.
Comment: The adjuvant endocrine therapy recommendations in this update are for all women, irrespective of any specific clinical subset or prognostic marker. AI therapy has not been evaluated in men, thus the continued recommendation that men with breast cancer receive adjuvant tamoxifen.
Data suggest that variability in tamoxifen metabolism affects the likelihood of cancer recurrence in patients treated with tamoxifen. Factors that contribute to this variability include concurrent use of other drugs that inhibit the CYP2D6 isoenzyme and pharmacogenetic variation (polymorphisms) in CYP2D6 alleles. It is not yet known whether these variations account for differences in outcomes among patients treated with tamoxifen.
Available data on CYP2D6 pharmacogenetics are insufficient to recommend testing as a tool to determine an adjuvant endocrine strategy. Patients who clearly benefit from known CYP2D6 inhibitors might consider avoiding tamoxifen because of potential pharmacologic interactions. Conversely, patients who receive tamoxifen may prefer to avoid concurrent use of known CYP2D6 inhibitors if suitable alternatives are available.”
Please review the complete therapeutic recommendations that are located here:
(3).
Table 3. CPIC (2018). Dosing Recommendations for Tamoxifen based on CYP2D6 Phenotype| Activity score – for a description of how scores are calculated, please see the “Genetic Testing” section below. a
Rating scheme described in the CPIC Supplement (4). |
| b
. CPIC has generally classified individuals with an activity score of 1 as a “normal metabolizer.” However, in the case of tamoxifen, prescribing recommendations for those with an activity score (AS) of 1.0 are allele dependent, based on the presence of the *10 allele. Those individuals with an AS of 1.0 on the basis of a *10 allele are provided a “moderate” recommendation. In contrast, prescribing recommendations for those with an activity score of one based on the presence of CYP2D6 alleles other than *10 are graded as “optional” because the recommendations are primarily extrapolated from evidence generated from *10 individuals (i.e., limited data for clinical outcomes and pharmacokinetics for this group). |
| This Clinical Pharmacogenetics Implementation Consortium (CPIC) table is adapted from (4) |
| Phenotype | Implications | Therapeutic recommendationb
| Classification of recommendationa
|
|---|
| Metabolizer status | Activity score |
|---|
| CYP2D6 ultrarapid metabolizer | >2.0 | Therapeutic endoxifen concentrations | Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day). | Strong |
| CYP2D6 normal metabolizer | 1.5–2.0 | Therapeutic endoxifen concentrations | Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day). | Strong |
| CYP2D6 normal metabolizer or intermediate metabolizer (controversy remains)b
| 1.0
(no *10 allele present)b
| Lower endoxifen concentrations compared with normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared with normal metabolizers. | Consider hormonal therapy such as an aromatase inhibitor for post-menopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype. If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day). Avoid CYP2D6 strong to weak inhibitors. | Optionalb
|
| CYP2D6 normal metabolizer or intermediate metabolizer (controversy remains)b
| 1.0
(*10 allele present)b
| Lower endoxifen concentrations compared with normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared with normal metabolizers. | Consider hormonal therapy such as an aromatase inhibitor for post-menopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype. If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day). Avoid CYP2D6 strong to weak inhibitors. | Moderateb
|
| CYP2D6 intermediate metabolizer | 0.5 | Lower endoxifen concentrations compared with normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared with normal metabolizers. | Consider hormonal therapy such as an aromatase inhibitor for post-menopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype. If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day). Avoid CYP2D6 strong to weak inhibitors. | Moderate |
| CYP2D6 poor metabolizer | 0 | Lower endoxifen concentrations compared with normal metabolizers; higher risk of breast cancer recurrence, event-free and recurrence-free survival compared with normal metabolizers. | Recommend alternative hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype and based on knowledge that CYP2D6 poor metabolizers switched from tamoxifen to anastrozole do not have an increased risk of recurrence. Note, higher dose tamoxifen (40 mg/day) increases but does not normalize endoxifen concentrations and can be considered if there are contraindications to aromatase inhibitor therapy. | Strong |
1
The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance to nomenclature standards, where necessary. We have given the full name of abbreviations where necessary, other author insertions are shown in square brackets.
2
The 2014 ASCO practice guideline focused update does not address pharmacogenetic testing (JCO July 20, 2014 vol. 32 no. 212255-2269).