Technology Evaluation
Center (TEC)

CYP2D6 Pharmacogenomics of Tamoxifen Treatment

Executive Summary

Background

Tamoxifen is prescribed as a component of adjuvant endocrine therapy to prevent endocrine receptor-positive breast cancer recurrence, as treatment of metastatic breast cancer, and to prevent disease in high-risk populations and in women with ductal carcinoma in situ (DCIS). The cytochrome P450 (CYP450) metabolic enzyme CYP2D6 has a major role in tamoxifen metabolism. The CYP2D6 gene is polymorphic; variant DNA gene sequences resulting in proteins with reduced or absent enzyme function may be associated with lower plasma levels of active tamoxifen metabolites, which could have an impact on tamoxifen treatment efficacy.

Objective

This Assessment evaluates the evidence for CYP2D6 genotyping, compared to no testing, to direct treatment regimen choices for patients at high risk for primary breast cancer or breast cancer recurrence, and improve survival outcomes.

Search Strategy

MEDLINE® was searched (via PubMed) using the search string "tamoxifen"[MeSH®] AND ("pharmacogenetics"[MeSH®] OR "cytochrome P450 enzyme system"[MeSH®]) through January 2008. Clinical trials, recent reviews (2004–2008), editorials, and letters related to the pharmacogenomics of tamoxifen were retrieved. In addition, text and reference lists of retrieved papers were examined for additional relevant articles.

Selection Criteria

Full-length, peer-reviewed papers reporting studies of postmenopausal women undergoing endocrine therapy whose treatment regimen selection is based on CYP2D6 genotyping versus usual selection methods, OR, studies of the association of CYP2D6 genotype with intermediate (e.g., tamoxifen active metabolite levels) or final outcomes (e.g., time to recurrence, survival) were selected for review.

Main Results

One U.S. Food and Drug Administration (FDA) -cleared test for CYP2D6 genotyping has consistent evidence of analytic validity (i.e., technical accuracy and reliability).

Evidence for clinical validity (i.e., association of CYP2D6 genotype with clinical outcomes) consists of the following elements grouped into the beginning of two possible evidence chains, A and B:

A.

Association of genotype with plasma levels of active tamoxifen metabolite: Three prospective cohort studies of adjuvant tamoxifen treatment provide consistent evidence that CYP2D6 nonfunctional variant alleles that render patients intermediate (one variant allele) or poor (two variant alleles) metabolizers of tamoxifen (intermediate [IMs] and poor [PMs] metabolizers, respectively), are associated with significantly reduced plasma levels of endoxifen, the most bioavailable of tamoxifen active metabolites. However, endoxifen levels overlap across all genotypes, suggesting that CYP2D6 genetic variability does not explain all variability in endoxifen levels. One study suggests that reduced-function variant homozygotes, but not heterozygotes, also have significantly reduced circulating endoxifen. Co-administration of a potent CYP2D6 inhibitor to CYP2D6 homozygous wild-type patients (extensive metabolizers [EMs]) is associated with endoxifen levels near those of patients who are poor metabolizers.

AND

Association of in vivo endoxifen levels with clinical outcomes: The relationship between endoxifen plasma concentrations and clinical outcomes has not been established.

B.

Association of genotype with clinical outcomes: an ideal study would compare tamoxifen-treated women versus those not receiving tamoxifen, with stratification by CYP2D6 genotype to see if PMs derive less benefit from tamoxifen than EMs. One group* conducted such a study retrospectively, on archived samples from a randomized controlled trial of tamoxifen treatment. Paradoxically, they found that EMs treated with tamoxifen received no statistically significant clinical benefit compared to EMs not treated with tamoxifen, and that carriers of a CYP2D6*4 nonfunctional variant allele obtained significant benefit from tamoxifen treatment. There were several limitations to this study such that results are questionable. The other included studies enrolled only tamoxifen-treated women and evaluated outcomes by CYP2D6 genotype. Evidence from two higher-quality trials of adjuvant tamoxifen (Table) suggests that women who are CYP2D6 IMs or PMs, whether by genotype or by co-medication with CYP2D6 inhibitors, treated with tamoxifen have significantly reduced time to recurrence and recurrence-free survival (but not overall survival) compared to EMs in multivariate analyses adjusted for other parameters of disease prognosis. The strength of these associations was marginal and might be stronger and more convincing if PMs alone could be compared to EMs, but PM numbers were insufficient. Few variant alleles were typed in these studies, and samples negative for variant alleles were assumed to be wild-type EMs; more extensive genotyping and better categorization might also strengthen results. Three other studies were of lesser quality and provide conflicting evidence.

Table.  Summary of Two Studies of CYP2D6 Genotype and Clinical Outcomes

Abbreviations:  TAM, tamoxifen; EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer; HR, hazard ratio; TTR, time to recurrence; RFS, recurrence-free survival; OS, overall survival;  NCCTG, North Central Cancer Treatment Group.

Goetz MP, Knox SK, Suman VJ et al.  (2007).  The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.  Breast Cancer Res Treat, 101(1):113-21.

Schroth W, Antoniadou L, Fritz P et al.  (2007).  Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes.  J Clin Oncol, 25(33):5187-93.

There is no direct evidence of clinical utility (whether use of CYP2D6 genotype testing for endocrine therapy regimen selection improves recurrence and survival outcomes). Two indirect evidence chains, A and B (above), can be constructed; the final element for both in postmenopausal women would be evidence that CYP2D6 PMs treated with aromatase inhibitors (AI) alone have outcomes at least as good as CYP2D6 EMs treated with AI alone or AI plus tamoxifen. In premenopausal women who are CYP2D6 PMs, ovarian ablation or suppression, which confers a significant benefit compared to no therapy, might be added to or might replace tamoxifen. Evidence chain A depends on demonstrating a significant association between in vivo endoxifen levels and clinical outcomes; this evidence does not exist. Evidence chain B depends on the association of genotype with clinical outcomes. As noted, there are several limitations to this evidence, and as a result it is judged insufficient to support clinical utility.

Author's Conclusions and Comments

The hypothesis examined in this Assessment is that CYP2D6 poorer metabolizers, whether by genotype or by co-administration of CYP2D6 inhibitory medication, have reduced tamoxifen metabolism and lower endoxifen levels compared to better metabolizers, and as a direct result have poorer clinical outcomes. This hypothesis is based on the assumption, not yet supported by evidence, that some level of endoxifen is sufficient and necessary for tamoxifen efficacy, and that this level is not achieved in genotypic and functional CYP2D6 PMs, and possibly not in some IMs. It seems feasible to propose such a study in tamoxifen-treated populations of completed clinical trials, where appropriate specimens are available. The advantage of such a study is that the metabolite itself, rather than the activity of the enzyme producing it, would be directly measured in relation to clinical outcomes. Because tamoxifen metabolism is complex and CYP2D6 does not appear to account for all variability in endoxifen levels, it is conceivable that polymorphisms in other tamoxifen metabolic pathway enzymes may affect active metabolite levels, and direct measurement of the metabolite(s) itself may be the better predictor of benefit from tamoxifen treatment. However, since it takes 8 weeks for tamoxifen metabolites to reach steady-state concentrations, measuring metabolite levels is not practical for clinical applications outside of a retrospective study.

Additionally or alternatively, larger studies of the CYP2D6 genotype-clinical outcomes association are needed to expand and verify initial results, and to accurately identify the exact genotypes that have poorer outcomes and would best benefit from AI treatment alone, versus those that would best benefit from regimens including tamoxifen.

Multiple enzyme genotypes may be needed to confidently predict tamoxifen versus AI treatment benefit; however, there are little data at present to recommend any genotype combinations.

Based on the available evidence, the Blue Cross and Blue Shield Medical Advisory Panel made the following judgments about whether CYP2D6 genotyping for directing endocrine therapy regimen selection for women at high risk for primary breast cancer or breast cancer recurrence meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.

1. The technology must have final approval from the appropriate government regulatory bodies.

The Roche AmpliChip CYP450 Test is cleared by the FDA to determine patients' CYP2D6 and CYP2C19 genotypes.

CYP2D6 genotyping assays are also available as laboratory-developed services. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratories offering such tests as a clinical service must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA) and must be licensed by CLIA for high-complexity testing. While the FDA has technical authority to regulate home-brew tests, to date there has been no active oversight with the possible exception of "in vitro diagnostic multivariate index assay" (IVDMIA) devices, for which a guidance document is currently in the draft stage.

The FDA has been considering updating the product labeling for tamoxifen with information or recommendations regarding CYP2D6 genotyping and impact on tamoxifen efficacy. On October 18, 2006, the FDA held an Advisory Committee meeting to answer specific questions regarding the evidence and recommendations for the label update; the members of the Advisory Committee recommended including information on CYP2D6 genotypes and potential effect on patient outcomes, and information on CYP2D6 genotyping tests. The members did not reach a consensus as to whether testing should be recommended or considered as an option. Since the Advisory Committee meeting, AstraZeneca, the brand name (Nolvadex®) manufacturer, has ceased producing tamoxifen and is no longer maintaining the prescribing information. As of the date of this Assessment, no direction has come from the FDA regarding revised labeling of generic versions of tamoxifen to include CYP2D6 genotyping information.

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

There is no direct evidence of clinical utility. Two indirect evidence chains can be constructed. One depends on demonstrating a significant association between endoxifen and clinical outcomes; this evidence does not exist. The other depends on the association of genotype with clinical outcomes; there are several limitations to this evidence, and, as a result, it is judged insufficient to support clinical utility.

3. The technology must improve the net health outcome; and

4. The technology must be as beneficial as any established alternatives.

There is insufficient evidence to permit conclusions regarding the use of CYP2D6 genotyping for directing endocrine therapy regimen selection for women at high risk for or with breast cancer.

5. The improvement must be attainable outside the investigational settings.

Whether or not the use of CYP2D6 genotyping for directing endocrine therapy regimen selection for women at high risk for or with breast cancer improves health outcomes has not been demonstrated in the investigational setting.

Based on the above, CYP2D6 genotyping does not meet the TEC criteria for directing endocrine therapy regimen selection for women at high risk for primary breast cancer or breast cancer recurrence.

*Wegman P, Vainikka L, Stal O et al. (2005). Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res, 7(3):R284-90.

Full Study

CYP2D6 Pharmacogenomics of Tamoxifen Treatment

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4-hydroxytamoxifen; adjuvant; AI; allele; AmpliChip; analytic validity; anastrozole; aromatase inhibitor; bioavailability; bioavailable; breast cancer; CLIA; clinical utility; clinical validity; coadministration; co-administration; CYP; CYP2D6; cytochrome p450; DCIS; desmethyltamoxifen; ductal carcinoma in situ; EM; endocrine; endoxifen; estrogen receptor; exemestane; extensive metabolizers; genotype; IM; intermediate metabolizers; IVDMIA; letrozole; metabolites; Nolvadex; nonfunctional; perimenopausal; pharmacogenetics; pharmacogenomics; phenotype; PM; polymorphisms; poor metabolizers; postmenopausal; premenopausal; selective serotonin reuptake inhibitor; tamoxifen; ultrarapid; wild-type;