Abstract P3-12-05: Serum levels of the active tamoxifen metabolite Z-4OHtam is predictive of long-term survival in luminal B subtype of breast cancer patients
Authors: T Helland, H Søiland, S Hustad, TL Lash, JT Kvaløy, A Renolen, E Borgen, E Bifulco, N Henne, EA Lien, G Mellgren, B Naume, EA Janssen
Journal: Cancer Research (2018)

Abstract 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 &amp;gt;3.26 nM (p&amp;lt;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.