CYP2D6 test, tamoxifen and breast cancer – pro

Tamoxifen is transformed to the anti-estrogen, endoxifen, by the cytochrome P450 (CYP) 2D6 enzyme. CYP2D6 genetic variation markedly reduce endoxifen plasma concentrations in tamoxifen-treated patients. CYP2D6 metabolism is an independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer in some studies. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women.

On October 18, a presentation of this study and related historical data by Dr. Goetz to the Food and Drug Administration led to an advisory committee unanimously recommending a label change for tamoxifen. This change would include information about the increased risk both from genetic factors and drug interactions affecting CYP2D6. However, the relationship between endoxifen plasma concentrations and clinical outcomes has not been established.

Thus, CYPD26 inhibitors should be avoided by patients on tamoxifen but the test cannot be routinely recommended yet to select treatment. TEC assessment by BCBS concluded:” 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.” A recent article and editorial in the Journal of Clinical Oncology confirmed that the available evidence is not sufficient to routinely recommend this testing. …”that a number of reported studies have been confounded as a result of a variety of biases and do not provide the level of evidence that is needed to recommend CYP2D6 genotyping. In fact, all published pharmacogenetic studies, by virtue of their retrospective nature (including prospective-retrospective studies), are prone to limitations; therefore, it is a minimum requirement that sample size, population stratification, quality of genotyping, and allele coverage, as well as correct genotype-phenotype assignment are vigorously addressed. Thus, studies that are based solely on the availability of samples are of little value”.

I would add that in 2009 ASCO meeting,  Aubert and colleagues presented in the clinically significant drug interaction between TAM and known CYP2D6 inhibitors. This resulted in a significant 1.9 fold higher BrCa recurrence within 2 years of initiating TAM therapy. This study has been extensively discussed but it had not resulted in any guideliens or consensus recommendations. As such, it appears premature to routinely test patients for this mutation since there is no accepted consensus on what to do with the results of the test. A 2011 Technology Review concluded: “This is a relatively new area of research that is evolving rapidly and, although international consortia are collaborating, the data are limited and conflicting. Therefore, it is not possible to recommend pharmacogenetic testing in this patient population. Future research needs to focus on which alleles (including, or in addition to, those related to CYP2D6) reflect patient response, the link between endoxifen levels and clinical outcomes, and the appropriate pathways for implementation of such pharmacogenetic testing in patient care pathways.”

Kiyotani K, Mushiroda T, Imamura CK, Hosono N, Tsunoda T, Kubo M, Tanigawara Y, Flockhart DA, Desta Z, Skaar TC, Aki F, Hirata K, Takatsuka Y, Okazaki M, Ohsumi S, Yamakawa T, Sasa M, Nakamura Y, Zembutsu H. Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients.J Clin Oncol. 2010 Mar 10;28(8):1287-93.

Aubert, R. E., Stanek, E. J., Yao, J., Teagarden, J. R., Subar, M., Epstein, R. S., Skaar, T. C., Desta, Z., Flockhart, D. A. Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors  J Clin Oncol (Meeting Abstracts) 2009 27: CRA508

MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM, Desta Z, Nguyen A, Flockhart DA, Perez EA, Ingle JN.The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.Breast Cancer Res Treat. 2007 Jan;101(1):113-21.

Hiltrud Brauch et al, Tamoxifen Use in Postmenopausal Breast Cancer: CYP2D6 Matters, JCO January 10, 2013 vol. 31 no. 2 176-180

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