The End of ENDoxifen Metabolite and CYP2D6 Testing in Tamoxifen-Treated Women?
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This JCO Podcast provides observations and commentary on the JCO article “Tamoxifen pharmacogenetics and metabolism: Results from the prospective CYPTAM study” by Sanchez-Spitman et al. My name is Vered Stearns, and I am a Professor of Oncology and Co-Director of the Breast and Ovarian Cancer Program at the Kimmel Cancer Center at Johns Hopkins in Baltimore, Maryland. My oncologic specialty is medical oncology. In the paper that accompanies this podcast, the authors report results of a prospective clinical study designated CYPTAM, which was designed to correlate endoxifen serum concentrations and outcomes of women prescribed adjuvant tamoxifen. The investigators enrolled 667 women with breast cancer who were initiating tamoxifen or who have been on tamoxifen for fewer than 12 months. The investigators obtained blood samples for CYP2D6 genotyping using the Amplichip CYP450 Test, and measured steady state concentrations of endoxifen with a high-performance liquid chromatography-tandem mass spectrometry. Co-primary endpoints included association of recurrence-free survival with endoxifen concentrations and with CYP2D6 genotypes. The patients were censored at the time of tamoxifen-discontinuation in case of a transition to an aromatase inhibitor. Several additional endpoints included disease-free survival, complete relapse-free survival, complete disease-free survival and overall survival. The statistical analysis plan was designed as a gate-keeper analysis for the co-primary objectives. Only if an association was found with a p-value below 0.05, were the remaining objectives considered.

The authors were not able to demonstrate an association between endoxifen concentrations and recurrence-free survival on tamoxifen. They also were not able to demonstrate an association either when exploring endoxifen concentrations in quartiles or when considering other thresholds. Likewise, there was no association between CYP2D6 genotypes and recurrence-free survival.

Almost two decades ago, researchers recognized that the absence or inhibition of the CYP2D6 enzyme is associated with very low concentrations of endoxifen, a potent and abundant anti-estrogen metabolite of tamoxifen. Whether low concentrations of endoxifen predict an inferior survival outcome has not been definitively determined. Multiple retrospective and small prospective studies evaluated CYP2D6 genotypes and survival outcomes and have provided mixed evidence. Clinicians have, therefore, wondered whether CYP2D6 genotype testing or endoxifen monitoring will assist in treatment recommendations. The CYPTAM investigators attempted to prospectively correlate endoxifen serum concentrations and outcomes for women taking tamoxifen.

The CYPTAM study is associated with several limitations, and, therefore, it does not provide a definitive answer to the controversy. For example, women were enrolled in the study either before starting tamoxifen or up to 12 months after initiation of the drug. This strategy could have led to incomplete baseline data and to the exclusion of individuals with early recurrences. In addition, about two-thirds of study participants transitioned to aromatase inhibitors following a short course of tamoxifen. The sequential administration of tamoxifen and aromatase inhibitors is superior to tamoxifen alone. Some of the patients who transitioned to aromatase inhibitors could have suffered a recurrence had they have stayed on tamoxifen alone. Furthermore, the authors did not have information regarding concomitant CYP2D6 inhibitor use. CYP2D6 inhibitors are commonly co-administered with tamoxifen and can contribute to misclassification of the CYP2D6 phenotype. 

The challenge moving forward is that single agent adjuvant tamoxifen is rarely used. Most postmenopausal women with hormone receptor-positive breast cancer are recommended an  aromatase inhibitor instead of, or in sequence with, tamoxifen. Premenopausal women with high risk hormone receptor-positive tumors are recommended ovarian suppression with tamoxifen or an aromatase inhibitor. Women prescribed tamoxifen alone are usually at extremely low risk of recurrence, and a prospective study in this group of women will require a large number of participants to demonstrate differences between phenotypes. Given current practice, it may not be feasible to fully determine the role of endoxifen concentrations and CYP2D6 genotypes as predictors of tamoxifen efficacy.

Retrospective analyses that used samples obtained through large prospective studies, such as the Arimidex, Tamoxifen, Alone or in Combination and the Breast International Group 1-98, failed to demonstrate an association between CYP2D6 phenotypes and survival outcomes. Taken together, the data at present are insufficient to recommend CYP2D6 testing or analysis of metabolic profile in women for whom tamoxifen is considered. Indeed, clinical guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network do not recommend CYP2D6 genotyping. Moving forward, prospective studies of altered metabolism due to single nucleotide polymorphism, or administration of inhibitors, should be considered in clinical trials of standard and novel agents as these can lead to differences in drug efficacy and toxicity.

This concludes this JCO Podcast. Thank you for listening.