Authors' objectives:

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.

Authors' recommendations: 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.

Project Status: Completed

URL for project: http://www.bcbs.com/blueresources/tec/vols/23/cyp2d6-pharmacogenomics-of.html

Year Published: 2008

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: United States

Organisation Name: BlueCross BlueShield Association

Contact Address: BlueCross BlueShield Association, Technology Evaluation Center, 225 North Michigan Ave, Chicago, Illinois, USA. Tel: 888 832 4321

Contact Name: tec@bcbsa.com

Contact Email: tec@bcbsa.com

Copyright: BlueCross BlueShield Association (BCBS)