Serum concentrations of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients

Abstract

BackgroundControversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and robust approach. We have investigated the association between CYP2D6 genotypes, serum concentrations of active tamoxifen metabolites, and long-term outcome in tamoxifen treated breast cancer patients.MethodsFrom an original observational study comprising 817 breast cancer patients, 99 women with operable breast cancer were retrospectively included in the present study. This cohort of patients were adjuvantly treated with tamoxifen, had provided serum samples suitable for measuring tamoxifen metabolites, and were relapse-free at 3 years after the primary treatment commenced. The median follow-up time from this entry point to breast cancer death was 13.9 years. Patients were CYP2D6 genotyped and grouped into four CYP2D6 phenotype groups (Ultra rapid, extensive, intermediate, and poor metabolizers). Tamoxifen and nine metabolites were quantified in serum (n = 86) and compared with CYP2D6 phenotype groups and outcome.ResultsBreast cancer patients with low concentrations of Z-4-hydroxy-tamoxifen (Z-4OHtam; ≤ 3.26 nM) had a breast cancer-specific survival (BCSS) of 60% compared to 84% in patients with Z-4OHtam concentrations > 3.26 nM (p = 0.020, log-rank hazard ratio (HR) = 3.56, 95% confidence interval (CI) = 1.14–11.07). For patients with Z-4-hydroxy-N-desmethyl-tamoxifen (Z-endoxifen) levels ≤ 9.00 nM BCSS was 57% compared to 84% for patients with concentrations > 9.00 nM (p = 0.029, HR = 3.73, 95% CI = 1.05–13.22). Low concentrations of Z-4OHtam and Z-endoxifen were associated with poorer survival also after adjusting for clinically relevant variables (HR = 4.27, 95% CI = 1.35–13.58, and HR = 3.70, 95% CI = 1.03–13.25, respectively). Overall survival analysis showed similar survival differences for both active metabolites. The Antiestrogen Activity Score showed comparable effects, but did not improve the prognostic information.ConclusionsPatients with Z-4OHtam and Z-endoxifen concentrations lower than 3.26 nM or 9.00 nM, respectively, showed an adverse outcome. Our results suggest that direct measurement of active tamoxifen metabolite concentrations could be of clinical value. Validation in larger study cohorts is warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0916-4) contains supplementary material, which is available to authorized users.

Factors Affecting Tamoxifen Metabolism in Patients With Breast Cancer: Preliminary Results of the French PHACS Study

“…However a recent prospective study did not observe any significant association between clinical benefit of TAM and plasma ENDO exposure in 247 patients with neo-adjuvant and metastatic breast cancer, 13 corroborated by another recent study in 667 patients. 14 On the contrary, Helland et al 28 reported a correlation between ENDO and 4-OHTAM concentrations and long-term survival in 99 retrospectively analyzed patients with adjuvant breast cancer. Therefore, the clinical utility of therapeutic drug monitoring of ENDO concentrations remains uncertain.…”

Long-Term Administration of Conjugated Estrogen and Bazedoxifene Decreased Murine Fecal β-Glucuronidase Activity Without Impacting Overall Microbiome Community

“…This is a significant because women who are diagnosed with breast cancer use Tamoxifen for 5 or 10 years 41 . A recent study showed that lower active TAM metabolite concentrations in the serum was associated with poor outcome 42 . In combination with our data, showing TAM and 4-OH-Tam as potential substrates for bacterial GUS activity, this study suggests combined probiotic interventions might improve the outcome of breast cancer patients using tamoxifen by increasing serum active TAM metabolites.…”

Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics

“…D. Johnson et al, 2004;Lien et al, 1988) Accordingly, poor metabolizers appear to have the lowest plasma endoxifen levels. (Helland et al, 2017;Madlensky et al, 2011) Extensive metabolizers have slightly higher Z-endoxifen concentrations than intermediate metabolizers. (Madlensky et al, 2011) Some research suggests that the total concentration of tamoxifen and its metabolites is sufficiently high so as to overwhelm and inhibit estrogen binding to the estrogen receptor, irrespective of an individual's CYP2D6 genotype and phenotype.…”