Long-Term Selenium-Yeast Supplementation Does Not Affect Bone Turnover Markers: A Randomized Placebo-Controlled Trial.

Higher selenium status has been associated with lower bone turnover markers (BTM) in epidemiological studies. However, the long-term impact of selenium supplementation on BTMs has not been studied. We investigated the effects of selenium supplementation on BTMs including osteocalcin (OC), procollagen type I N-terminal propeptide (PINP), collagen type I cross-linked C-telopeptide (CTX), and bone alkaline phosphatase (BALP) in the short (6 months) and long term (5 years). A total of 481 Danish men and women (60-74 years) were randomized to receive placebo-yeast versus 100, 200, or 300 µg selenium as selenium-enriched yeast daily for 5 years. Plasma selenium concentration was measured using inductively coupled plasma mass spectrometry, and BTMs were measured in nonfasted samples at baseline, 6 months, and 5 years. Data were analyzed by ANCOVA to investigate the shape of the dose-response relationships. Covariates included age, body mass index, baseline selenium status, baseline BTM, smoking, alcohol, supplement use, and medication. Plasma selenium concentration (mean 86.5 µg/d at baseline) increased significantly with increasing selenium supplementation to 152.6, 209.1, and 253.7 µg/L after 6 months and remained elevated at 5 years (158.4, 222.4, and 275.9 µg/L for 100, 200, and 300 µg supplemental selenium/d, respectively (p < 0.001)). There was no change in plasma selenium concentration in the placebo-treated group. There was no significant effect of selenium supplementation on OC (6 months p = 0.37; 5 years p = 0.63), PINP (6 months p = 0.37; 5 years p = 0.79), CTX (6 months p = 0.91; 5 years p = 0.58) or BALP (6 months p = 0.17; 5 years p = 0.53). The relatively replete baseline selenium status in the study participants may explain this lack of effect. Testing in more deficient populations may provide further insights into the impact of selenium supplementation on bone health. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Leukocyte nadir as a predictive factor for efficacy of adjuvant chemotherapy in breast cancer. Results from the prospective trial SBG 2000-1.

Background: Retrospective studies have suggested that chemotherapy-induced leukopenia is associated with improved recurrence-free or overall survival. The SBG 2000-1 trial was designed to verify the favorable prognosis associated with chemotherapy-induced leukopenia in early breast cancer. Patients not experiencing chemotherapy-induced leukopenia were randomized into standard dosed or individually escalated chemotherapy doses based on the grade of leukopenia after a first standard dose.Patients and methods: 1452 women in Sweden and Denmark with operable node-positive or high-risk node-negative breast cancer aged 18-60 years were recruited to participate in this trial. Participants received a first FEC cycle at standard doses (600/60/600 mg/m2). Patients (n = 1052) with nadir leukopenia grade 0-2 after the first cycle were randomized between either 6 standard FEC or 6 tailored FEC courses with doses of epirubicin and cyclophosphamide escalated during courses 2 and 3 and thereafter aimed at achieving grade 3 leukopenia. Patients with nadir leukopenia grade 3-4 after the first course continued treatment with standard FEC. Results of the randomized comparison has been published previously. The present study focuses on chemotherapy-induced leukopenia as a covariable with outcome in randomized and non-randomized patients. The prognostic value of leukopenia after course 3, was studied in a Cox model adjusted for cumulative doses of epirubicin and cyclophosphamide. The association of chemotherapy-induced leukopenia with prognosis was a preplanned secondary endpoint for this trial.Results: The eight-year distant disease-free survival was 73%, 77%, 78% and 83% for patients with leucocyte nadir grade 0, 1, 2 and 3-4, respectively. Higher degree of leukopenia was highly significantly associated to improved distant disease-free survival (HR 0.84, 95% CI 0.74-0.96, p = .008) and overall survival (HR 0.87 (0.76-0.99, p = .032).Conclusion: This prospective study confirms that chemotherapy-induced leukopenia is a covariable with outcome in primary breast cancer, even after adjustment for chemotherapy doses.

Effect of selenium supplementation on changes in HbA1c: Results from a multiple-dose, randomized controlled trial.

AIM: To investigate the effect of selenium supplementation at different dose levels on changes in HbA1c after 6 months and 2 years in a population of low selenium status. MATERIALS AND METHODS: The Denmark PRECISE study was a single-centre, randomized, double-blinded, placebo-controlled, multi-arm, parallel clinical trial with four groups. In total, 491 volunteers aged 60 to 74 years were randomly assigned to treatment with 100, 200 or 300 µg selenium/day as selenium-enriched yeast or placebo-yeast. HbA1c measurements were available for 489 participants at baseline, 435 at 6 months, and 369 after 2 years of selenium supplementation. Analyses were performed by intention to treat. RESULTS: The mean (SD) age, plasma-selenium concentration, and blood HbA1c at baseline were 66.1 (4.1) years, 86.5 (16.3) ng/g and 36.6 (7.0) mmol/mol, respectively. During the initial 6-month intervention period, mean HbA1c (95% CI) decreased by 1.5 (-2.8 to -0.2) mmol/mol for 100 µg/d of selenium supplementation and by 0.7 (-2.0 to 0.6) mmol/mol for the 200 and 300 µg/d groups compared with placebo (P = 0.16 for homogeneity of changes across the four groups). After 2 years of selenium supplementation, HbA1c had decreased significantly in all treatment groups, with no difference between active treatment and placebo. CONCLUSIONS: Selenium supplementation in an elderly European population of low selenium status did not significantly affect HbA1c levels after 2 years. Our findings corroborate a possible U-shaped response of selenium supplementation on glucose metabolism.

Effect of long-term selenium supplementation on mortality: Results from a multiple-dose, randomised controlled trial.

BACKGROUND: Selenium, an essential trace element, is incorporated into selenoproteins with a wide range of health effects. Selenoproteins may reach repletion at a plasma selenium concentration of ~ 125 µg/L, at which point the concentration of selenoprotein P reaches a plateau; whether sustained concentrations higher than this are beneficial, or indeed detrimental, is unknown. OBJECTIVE: In a population of relatively low selenium status, we aimed to determine the effect on mortality of long-term selenium supplementation at different dose levels. DESIGN: The Denmark PRECISE study was a single-centre, randomised, double-blinded, placebo-controlled, multi-arm, parallel clinical trial with four groups. Participants were 491 male and female volunteers aged 60-74 years, recruited at Odense University Hospital, Denmark. The trial was initially designed as a 6-month pilot study, but supplemental funding allowed for extension of the study and mortality assessment. Participants were randomly assigned to treatment with 100, 200, or 300 µg selenium/d as selenium-enriched-yeast or placebo-yeast for 5 years from randomization in 1998-1999 and were followed up for mortality for a further 10 years (through March 31, 2015). RESULTS: During 6871 person-years of follow-up, 158 deaths occurred. In an intention-to-treat analysis, the hazard ratio (95% confidence interval) for all-cause mortality comparing 300 µg selenium/d to placebo was 1.62 (0.66, 3.96) after 5 years of treatment and 1.59 (1.02, 2.46) over the entire follow-up period. The 100 and 200 µg/d doses showed non-significant decreases in mortality during the intervention period that disappeared after treatment cessation. Although we lacked power for endpoints other than all-cause mortality, the effects on cancer and cardiovascular mortality appeared similar. CONCLUSIONS: A 300 µg/d dose of selenium taken for 5 years in a country with moderately-low selenium status increased all-cause mortality 10 years later. While our study was not initially designed to evaluate mortality and the sample size was limited, our findings indicate that total selenium intake over 300 µg/d and high-dose selenium supplements should be avoided.

Randomised controlled trial of the effect of long-term selenium supplementation on plasma cholesterol in an elderly Danish population.

Although cross-sectional studies have shown a positive association between Se and cholesterol concentrations, a recent randomised controlled trial in 501 elderly UK individuals of relatively low-Se status found that Se supplementation for 6 months lowered total plasma cholesterol. The Danish PRECISE (PREvention of Cancer by Intervention with Selenium) pilot study (ClinicalTrials.gov ID: NCT01819649) was a 5-year randomised, double-blinded, placebo-controlled trial with four groups (allocation ratio 1:1:1:1). Men and women aged 60-74 years (n 491) were randomised to 100 (n 124), 200 (n 122) or 300 (n 119) µg Se-enriched yeast or matching placebo-yeast tablets (n 126) daily for 5 years. A total of 468 participants continued the study for 6 months and 361 participants, equally distributed across treatment groups, continued for 5 years. Plasma samples were analysed for total and HDL-cholesterol and for total Se concentrations at baseline, 6 months and 5 years. The effect of different doses of Se supplementation on plasma lipid and Se concentrations was estimated by using linear mixed models. Plasma Se concentration increased significantly and dose-dependently in the intervention groups after 6 months and 5 years. Total cholesterol decreased significantly both in the intervention groups and in the placebo group after 6 months and 5 years, with small and nonsignificant differences in changes in plasma concentration of total cholesterol, HDL-cholesterol, non-HDL-cholesterol and total:HDL-cholesterol ratio between intervention and placebo groups. The effect of long-term supplementation with Se on plasma cholesterol concentrations or its sub-fractions did not differ significantly from placebo in this elderly population.

Does selenium supplementation affect thyroid function? Results from a randomized, controlled, double-blinded trial in a Danish population.

OBJECTIVE: Selenium is present in the active site of proteins important for thyroid hormone synthesis and metabolism. The objective of this study is to investigate the effect of selenium supplementation in different doses on thyroid function, under conditions of suboptimal dietary selenium intake. DESIGN: The Danish PREvention of Cancer by Intervention with SElenium pilot study (DK-PRECISE) is a randomized, double-blinded, placebo-controlled trial. A total of 491 males and females aged 60-74 years were randomized to 100 µg (n=124), 200 µg (n=122), or 300 µg (n=119) selenium-enriched yeast or matching yeast-based placebo tablets (n=126). A total of 361 participants, equally distributed across treatment groups, completed the 5-year intervention period. METHODS: Plasma samples were analyzed for selenium and serum samples for TSH, free triiodothyronine (FT3), and free thyroxine (FT4) at baseline, and after 6 months, and 5 years of supplementation. RESULTS: Plasma selenium concentrations increased significantly and dose-dependently in treatment groups receiving selenium (P<0.001). Serum TSH and FT4 concentrations decreased significantly and dose-dependently by 0.066 mIU/l (P=0.010) and 0.11 pmol/l (P=0.015), respectively, per 100 µg/day increase, with insignificant differences between 6 months and 5 years. No significant effects were found for FT3 and FT3:FT4 ratio. CONCLUSIONS: In euthyroid subjects, selenium supplementation minutely and dose-dependently affects thyroid function, when compared with placebo, by decreasing serum TSH and FT4 concentrations. Based on these findings, selenium supplementation is not warranted under conditions of marginal selenium deficiency. However, a role for selenium supplementation in the treatment of autoimmune thyroid diseases is still unresolved.

One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer.

PURPOSE: We report the long-term results of a randomised trial comparing tamoxifen with tamoxifen plus cyclophosphamide, methotrexate and fluorouracil (CMF) in postmenopausal high-risk breast cancer patients. In addition, we analyse the prognostic and predictive value of centrally assessed subtypes. METHODS: Postmenopausal patients with breast cancer and positive nodes, deep invasion or size exceeding 5 cm were randomly assigned to 1 year of tamoxifen, or cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2 and fluorouracil 600 mg/m2 intravenously on day 1 every 4 weeks for nine cycles plus tamoxifen (CMFT). Tissue microarrays were constructed retrospectively and oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and proliferation-related Ki-67 antigen (Ki67) status were assessed. RESULTS: From October 1982 through March 1990 we randomised 1445 patients and 969 (67%) were eligible for the biomarker analysis. At 10-years 936 women had suffered a disease-free survival (DFS) event (tamoxifen, 495 events in 686 patients; CMFT, 441 events in 642 patients). The addition of CMF to tamoxifen significantly improved DFS (adjusted hazard ratio 0.82; 95% confidence interval (CI) 0.71-0.93; P = 0.003) but not overall survival (adjusted hazard ratio 0.95; 95% CI 0.85-1.08; P = 0.44). DFS was superior in Luminal A tumours (ER or PgR positive, HER2 negative and Ki67 ≤ 14%) when compared to Luminal B or non-luminal (ER and PgR negative) tumours. There was no statistical evidence of heterogeneity by subtype in the benefit from CMF (P(interaction) = 0.45). CONCLUSION: CMF added to 1 year of tamoxifen reduces the risk of a DFS event. The benefit from CMF was not significantly different in Luminal A and B subtypes.

DBCG trial 89B comparing adjuvant CMF and ovarian ablation: similar outcome for eligible but non-enrolled and randomized breast cancer patients.

INTRODUCTION: A cohort of premenopausal patients with primary hormone receptor positive breast cancer was prospectively identified to be eligible for the DBCG 89B trial. We perform a long-term follow-up and evaluate the external validity of the trial. MATERIAL AND METHODS: Following registration in a population-based registry, patients were invited to be randomized to ovarian ablation (OA) versus nine courses of three-weekly cyclophosphamide, methotrexate and 5-fluorouracil (CMF). The same procedures were used in all patients, including report forms, central review, querying, and analysis of data. Multivariate analysis was used to adjust for differences in base-line characteristics. RESULTS: Participation in the randomization varied according to center and time period. One thousand six hundred and twenty eight eligible patients were registered and 525 randomized in the DBCG 89B trial. Median estimated follow-up was 9.5 years for disease-free survival and 12.1 years for overall survival. Non-enrolled patients had a disease-free and overall survival similar to randomized patients. Within 5 years of surgery, results were similar following OA and CMF, but disease-free survival was significant inferior with OA more than five years after surgery, adjusted hazard ratio 1.38 (95% CI 1.03 to 1.85; p=0.03). This convened ten years after surgery to an inferior survival with OA, and the adjusted hazard ratio was 2.37 (95% CI 1.43 to 3.91; p<0.01). DISCUSSION: This prospective cohort study indicates that eligible patients not participating in the DBCG 89B trial had a similar disease-free and overall survival as participants. Survival was similar after OA and CMF in the first ten years, but became inferior in the OA group 10 or more years after surgery.

Bisphosphonate treatment in primary breast cancer: results from a randomised comparison of oral pamidronate versus no pamidronate in patients with primary breast cancer.

PURPOSE AND PATIENTS: During the period from January 1990 to January 1996 a total of 953 patients with lymph node negative primary breast cancer were randomised to oral pamidronate (n=460) 150 mg twice daily for 4 years or no adjuvant pamidronate (n=493) in order to investigate whether oral pamidronate can prevent the occurrence of bone metastases and fractures. The patients received adjuvant chemotherapy, loco-regional radiation therapy, but no endocrine treatment. RESULTS: During the follow-up period the number of patients with pure bone metastases was 35 in the control group and 31 in the pamidronate group. The number of patients with a combination of bone and other distant metastases were 22 in the control group and 20 in the pamidronate group. The hazard rate ratio for recurrence in bone in the pamidronate group compared to the control group was 1.03 (95% confidence interval 0.75-1.40) and p=0.86. No effect was observed on overall survival. In a small subgroup of 27 patients from the study, 12 of whom were treated with pamidronate a significant bone preserving effect was observed on bone mineral density in the lumbar spine, but not in the proximal femur. CONCLUSION: The results from the trial do not support a beneficial effect of oral pamidronate on the occurrence of bone metastases or fractures in patients with primary breast cancer receiving adjuvant chemotherapy.

Effect of long-term selenium yeast intervention on activity and gene expression of antioxidant and xenobiotic metabolising enzymes in healthy elderly volunteers from the Danish Prevention of Cancer by Intervention by Selenium (PRECISE) pilot study.

Numerous mechanisms have been proposed to explain the anti-carcinogenic effects of Se, among them altered carcinogen metabolism. We investigated the effect of Se supplementation on activities of glutathione peroxidase (GPX), glutathione reductase (GR) and glutathione S-transferase (GST) in different blood compartments, and expression of selected phase 1 and phase 2 genes in leucocytes (GPX1, gamma-glutamylcysteine ligase catalytic subunit (GCLC), AP-1 transcription factor Fos-related antigen 1 (Fra1), NAD(P)H:quinone oxidoreductase (NQO1), and aryl hydrocarbon receptor repressor (AhRR)). Healthy elderly Danes (n 105; age 71.3 (SD 4.26) years; 36% reporting use of multivitamin/mineral supplements) participated and were supplemented daily for 5 years with placebo, 100 microg, 200 microg or 300 microg Se as Se-enriched yeast (SelenoPrecise). Blood samples were collected after 5 years of intervention. When all four groups were compared we found no effect of Se supplementation on plasma GPX or GR, on erythrocyte GPX, GR or GST, or on thrombocyte GR or GST. We found increased thrombocyte GPX activity at the two highest dosage levels in women only, but not in men. No effects on GPX1, NQO1 or AhRR gene expression were found. When all Se-supplemented groups were pooled we found significant down regulation of the expression of some phase 2 genes (GCLC, Fra1). A significant increase in AhRR gene expression with smoking was found but was independent of Se supplementation. Down regulation of phase 2 genes could increase the risk of cancer. However, further studies are needed to establish whether the observed effect in leucocytes reflects a similar expression pattern in target tissues.

Similar efficacy for ovarian ablation compared with cyclophosphamide, methotrexate, and fluorouracil: from a randomized comparison of premenopausal patients with node-positive, hormone receptor-positive breast cancer.

PURPOSE: To compare the efficacy of ovarian ablation versus chemotherapy in early breast cancer patients with hormone receptor-positive disease. PATIENTS AND METHODS: We conducted an open, randomized, multicenter trial including premenopausal breast cancer patients with hormone receptor-positive tumors and either axillary lymph node metastases or tumors with a size of 5 cm or more. Patients were randomly assigned to ovarian ablation by irradiation or to nine courses of chemotherapy with intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) administered every 3 weeks. RESULTS: Between 1990 and May 1998, 762 patients were randomly assigned, and the present analysis is based on 358 first events. After a median follow-up time of 8.5 years, the unadjusted hazard ratio for disease-free survival in the ovarian ablation group compared with the CMF group was 0.99 (95% CI, 0.81 to 1.22). After a median follow-up time of 10.5 years, overall survival (OS) was similar in the two groups, with a hazard ratio of 1.11 (95% CI, 0.88 to 1.42) for the ovarian ablation group compared with the CMF group. CONCLUSION: In this study, ablation of ovarian function in premenopausal women with hormone receptor-positive breast cancer had a similar effect to CMF on disease-free and OS. No significant interactions were demonstrated between treatment modality and hormone receptor content, age, or any of the well-known prognostic factors.