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.

Rhythms are intrinsic to endocrine systems, and disruption of these hormone oscillations occurs at very early stages of the disease. Because adrenal hormones are secreted with both circadian and ultradian periods, conventional single–time point measurements provide limited information about rhythmicity and, crucially, do not provide information during sleep, when many hormones fluctuate from nadir to peak concentrations. If blood sampling is attempted overnight, then this necessitates admission to a clinical research unit, can be stressful, and disturbs sleep. To overcome this problem and to measure free hormones within their target tissues, we used microdialysis, an ambulatory fraction collector, and liquid chromatography–tandem mass spectrometry to obtain high-resolution profiles of tissue adrenal steroids over 24 hours in 214 healthy volunteers. For validation, we compared tissue against plasma measurements in a further seven healthy volunteers. Sample collection from subcutaneous tissue was safe, well tolerated, and allowed most normal activities to continue. In addition to cortisol, we identified daily and ultradian variation in free cortisone, corticosterone, 18-hydroxycortisol, aldosterone, tetrahydrocortisol and allo-tetrahydrocortisol, and the presence of dehydroepiandrosterone sulfate. We used mathematical and computational methods to quantify the interindividual variability of hormones at different times of the day and develop “dynamic markers” of normality in healthy individuals stratified by sex, age, and body mass index. Our results provide insight into the dynamics of adrenal steroids in tissue in real-world settings and may serve as a normative reference for biomarkers of endocrine disorders (ULTRADIAN, NCT02934399).

Here we report a series of close analogues of our recently published scaffold-based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R and R, and an aromatic group in R. While contraction/elongation of the guanidine carrying side chains (R and R) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2-ylmethyl moiety (R) resulted in an EC of 61μM (mixture of diastereoisomers) against wild-type CXCR4; thus, the antagonistic activity of these tripeptidomimetics seems to be amenable to optimization of the aromatic moiety. Moreover, for analogues carrying a naphth-2-ylmethyl substituent, we observed that a Pictet-Spengler like cyclization side reaction depended on the nature of the R substituent.

Background Tamoxifen (tam) is the main adjuvant endocrine treatment option in premenopausal breast cancer (BC) patients comprising luminal-like tumors. However, a significant proportion of tam-users will experience a relapse within 15 years of primary surgery. We postulate that some patients do not achieve the full clinical benefit of tam due to inter-individual differences in the metabolism of the drug and that the clinical relevance of this may be different between molecular subtypes of BC. Here, we have compared the prognostic value of threshold levels of active tam metabolites in PAM50 luminal (lum) A and B molecular subtypes. Material and Methods A number of 64 lum-like BC patients who were relapse-free 3 years after surgery, were retrospectively analyzed in the observational Oslo1 study. All patients received 20 mg tamoxifen daily for 5 years. Serum was obtained at the time of the 3 years follow-up. A sensitive and accurate LC-MS/MS method was developed and validated for the detection and quantification of tam and 9 metabolites in human serum. The median follow-up time from serum sampling to BC death or last follow-up was 13.9 years (0.6-16.5). Recurrence score and molecular subtype of the patients were determined on FFPE-tumor samples using the PAM50 classification algorithm. Results A linear trend was identified for the correlation between active metabolite Z-4OHtam and BCSS (p=0.021, HR=0.64, CI95=0.43–0.93). There was no linear association between the remaining metabolites and BC outcome. We further explored the possible association between survival and concentration thresholds for the active metabolites Z-4OHtam and Z-endoxifen and identified supervised cut off values representing low concentrations for Z-4OHtam (≤3.26 nM) and Z-endoxifen (≤9.00 nM). BC patients with low Z-4OHtam had a BCSS of 33.3% compared to 82.8% in patients with Z-4OHtam >3.26 nM (p<0.001, logrank; HR=6.83, CI 95=2.09-22.36). Lum status (A vs B; HR=5.50, CI95= 1.66-18.25) and Z-4OHtam concentration status (high vs low; HR=6.05, CI95=1.74-21.06) were the only factors left in the final multivariable model. A log-linear relationship between the ROR score and BCSS (p=0.002, HR=1.09, CI95=1.03–1.15) was identified after adjustment of clinically relevant variables and lum status was highly prognostic, (Lum A vs B; p=0.001, HR=5.2, CI=1.72-15.46). Therefore, we wanted to compare the prognostic value of the Z-4OHtam threshold in patients subgroups stratified by lum status. Low concentrations of Z-4OHtam were associated with poorer survival for patients in the lum B group only (HR=4.94, CI 95=1.16-21-02). For the lum A patients no significant association was found. Discussion Low levels (≤ 3.26 nM) of the active tam metabolite Z-4OHtam was associated with a poorer long-term outcome in tam-treated BC patients. However, when grouping patients according to the PAM50-based molecular subtype, this was only significant in patients belonging to the lum B subtype. Our results suggest that higher levels of active tam metabolites and thus better ER blockage are more important in the more aggressive lum B subtype. Citation Format: Helland T, Søiland H, Hustad S, Lash TL, Kvaløy JT, Renolen A, Borgen E, Bifulco E, Henne N, Lien EA, Mellgren G, Naume B, Janssen EA. Serum levels of the active tamoxifen metabolite Z-4OHtam is predictive of long-term survival in luminal B subtype of breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-05.

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