CBD-oil as a potential solution in case of severe tamoxifen-related side effects.

Tamoxifen may lead to bothersome side effects contributing to non-compliance and decreased quality of life. Patients searching for relief are increasingly turning to cannabinoids such as CBD-oil. However, CBD-oil might affect tamoxifen pharmacokinetics (PK) through CYP2D6 inhibition. The aims of this open-label, single-arm study were (1) to determine the PK profile of tamoxifen when using CBD-oil, and (2) to subsequently investigate whether CBD-oil has a beneficial influence on side effects. Study patients had to have steady-state endoxifen concentrations ≥16 nM (conservative threshold). PK sampling and side effect assessment was done at initiation of CBD-oil and 28 days thereafter. Bio-equivalence could be concluded if the 90% confidence interval (CI) for the difference in endoxifen AUC fell within the [-20%; +25%] interval. The effect of CBD-oil on side effects was evaluated using the FACT-ES questionnaire. Endoxifen AUC decreased after CBD-oil by 12.6% (n = 15, 90% CI -18.7%, -6.1%) but remained within bio-equivalence boundaries. The endocrine sub-scale of the FACT-ES improved clinically relevant with 6.7 points (n = 26, p < 0.001) and health-related quality of life improved with 4.7 points after using CBD (95% CI + 1.8, +7.6). We conclude that CBD-oil, if of good quality and with a dosage below 50 mg, does not have to be discouraged in patients using it for tamoxifen-related side effects. Clinical trial registration: International Clinical Trial Registry Platform (NL8786; https://www.who.int/clinical-trials-registry-platform ).

Influence of probenecid on endoxifen systemic exposure in breast cancer patients on adjuvant tamoxifen treatment.

Introduction: In breast cancer patients treated with the anti-estrogen tamoxifen, low concentrations of the active metabolite endoxifen are associated with more disease recurrence. We hypothesized that we could increase endoxifen concentrations by induction of its formation and inhibition of its metabolism by co-administration of probenecid. Methods: We conducted a crossover study and measured endoxifen concentrations in patients on steady-state tamoxifen monotherapy and after 14 days of combination treatment with probenecid. Eleven evaluable patients were included. Results: Treatment with tamoxifen and probenecid resulted in a 26% increase of endoxifen area under the plasma concentration-time curve from 0 to 24 h (AUC0-24h) compared to tamoxifen monotherapy (95% confidence interval [CI]: 8-46%; p < 0.01), while the maximum observed endoxifen concentration increased with 24% (95% CI: 7-44%; p < 0.01). The metabolic ratio of endoxifen to tamoxifen increased with 110% (95% CI: 82-143%; p < 0.001) after the addition of probenecid. Conclusion: Probenecid resulted in a clinically relevant increase of endoxifen concentrations in breast cancer patients treated with adjuvant tamoxifen. This combination therapy could provide a solution for patients with a CYP2D6-poor metabolizer phenotype or endoxifen concentrations below the threshold despite earlier tamoxifen dose.

Therapeutic Drug Monitoring of Endoxifen for Tamoxifen Precision Dosing: Feasible in Patients with Hormone-Sensitive Breast Cancer.

BACKGROUND: Endoxifen is the most important active metabolite of tamoxifen. Several retrospective studies have suggested a minimal or threshold endoxifen systemic concentration of 14-16 nM is required for a lower recurrence rate. The aim of this study was to investigate the feasibility of reaching a predefined endoxifen level of ≥ 16 nM (5.97 ng/mL) over time using therapeutic drug monitoring (TDM). METHODS: This prospective open-label intervention study enrolled patients who started treatment with a standard dose of tamoxifen 20 mg once daily for early breast cancer. An outpatient visit was combined with a TDM sample at 3, 4.5, and 6 months after initiation of the tamoxifen treatment. The tamoxifen dose was escalated to a maximum of 40 mg if patients had an endoxifen concentration < 16 nM. The primary endpoint of the study was the percentage of patients with an endoxifen level ≥ 16 nM at 6 months after the start of therapy compared with historical data, in other words, 80% of patients with endoxifen levels ≥ 16 nM with standard therapy. RESULTS: In total, 145 patients were included. After 6 months, 89% of the patients had endoxifen levels ≥ 16 nM, compared with a literature-based 80% of patients with endoxifen levels ≥ 16 nM at baseline (95% confidence interval 82-94; P = 0.007). In patients with an affected CYP2D6 allele, it was not always feasible to reach the predefined endoxifen level of ≥ 16 nM. No increase in tamoxifen-related adverse events was reported after dose escalation. CONCLUSION: This study demonstrated that it is feasible to increase the percentage of patients with endoxifen levels ≥ 16 nM using TDM. TDM is a safe strategy that offers the possibility of nearly halving the number of patients with endoxifen levels < 16 nM.

Impact of Curcumin (with or without Piperine) on the Pharmacokinetics of Tamoxifen.

Tamoxifen is a prodrug that is primarily metabolized into the pharmacologically active metabolite endoxifen and eventually into inactive metabolites. The herb curcumin may increase endoxifen exposure by affecting phase II metabolism. We compared endoxifen and tamoxifen exposure in breast cancer patients with or without curcumin, and with addition of the bio-enhancer piperine. Tamoxifen (20⁻30mg per day (q.d.)) was either given alone, or combined with curcumin (1200 mg three times daily (t.i.d.)) +/- piperine (10 mg t.i.d.). The primary endpoint of this study was the difference in geometric means for the area under the curve (AUC) of endoxifen. Genotyping was performed to determine CYP2D6 and CYP3A4 phenotypes. The endoxifen AUC0⁻24h decreased with 7.7% (95%CI: -15.4 to 0.7%; p = 0.07) with curcumin and 12.4% (95%CI: -21.9 to -1.9%; p = 0.02) with curcumin and piperine, compared to tamoxifen alone. Tamoxifen AUC0⁻24h showed similar results. For patients with an extensive CYP2D6 metabolism phenotype (EM), effects were more pronounced than for intermediate CYP2D6 metabolizers (IMs). In conclusion, the exposure to tamoxifen and endoxifen was significantly decreased by concomitant use of curcumin (+/- piperine). Therefore, co-treatment with curcumin could lower endoxifen concentrations below the threshold for efficacy (potentially 20⁻40% of the patients), especially in EM patients.

A randomized phase 2 study exploring the role of bevacizumab and a chemotherapy-free approach in HER2-positive metastatic breast cancer: The HAT study (BOOG 2008-2003), a Dutch Breast Cancer Research Group trial.

BACKGROUND: To explore the role of bevacizumab and a chemotherapy-free approach, the authors evaluated the combination of bevacizumab, trastuzumab, and paclitaxel (HAT) and the regimen of trastuzumab and bevacizumab (HA) with the addition of paclitaxel after progression (HA-HAT) as first-line treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. METHODS: In a noncomparative phase 2 trial, patients were randomized between HAT and HA-HAT. The primary endpoint was the progression-free rate at 1 year (1-year PFR). In the HA-HAT group, progression-free survival (PFS) was separately established for HA (PFS1) and HAT (PFS2). RESULTS: Eighty-four patients received HAT (n = 39) or HA-HAT (n = 45). The 1-year PFR was 74.4% (95% confidence interval [CI], 61.8%-89.4%) and 62.2% (95% CI, 49.6%-89.4%) in the HAT and HA-HAT arms, respectively. The median PFS was 19.8 months (95% CI, 14.9-25.6 months) in the HAT arm and 19.6 months (95% CI, 12.0-32.0 months) in the HA-HAT arm. In the HA-HAT arm, the median PFS1 was 10.4 months (95% CI, 6.2-15.0 months), and the median PFS2 was 8.2 months (95% CI, 7.0-12.6 months). The number and severity of adverse events were comparable between the arms. CONCLUSIONS: Both HAT and HA-HAT have promising activity in patients with HER2-positive metastatic breast cancer. In particular, starting with only targeted agents and delaying chemotherapy is worth further exploration. Cancer 2016;122:2961-2970. © 2016 American Cancer Society.