Incidence of invasive breast cancer in postmenopausal women after discontinuation of long-term raloxifene administration.

BACKGROUND: Postmenopausal women with osteoporosis had a 66% relative risk reduction for invasive breast cancer over 8 years of raloxifene therapy in the randomized, placebo-controlled 4-year MORE (Multiple Outcomes of Raloxifene Evaluation) trial and the CORE (Continuing Outcomes Relevant to Evista) trial, a 4-year follow-up to MORE. PATIENTS AND METHODS: The first post hoc analysis examined the effects of raloxifene on the cumulative incidence of invasive breast cancer on a yearly basis. Another analysis compared the incidence of invasive breast cancer in 3967 patients who continued raloxifene for 8 years (RLX-C, n = 2280), discontinued raloxifene after 4 years in MORE (RLX-D, n = 401), or took placebo (n = 1286) for a mean 2.9 years' treatment duration (57,338 patient-years). RESULTS: The unadjusted breast cancer incidence rate was 5.39 per 1000 patient-years in the placebo group compared with 2.26 in the RLX-C group (hazard ratio [HR], 0.41 [95% CI 0.21-0.81]) and 3.59 in the RLX-D group (HR, 0.69 [95% CI 0.23-2.01]). Because the choice of taking the study drug was not randomized in CORE, propensity scores were used to adjust for potential imbalances in baseline characteristics before CORE. Results after adjustment by the propensity score method were similar to the unadjusted results. CONCLUSION: This analysis suggests a persistent effect for breast cancer risk reduction in patients who discontinued raloxifene, although this conclusion is limited by the small sample size.

Effect of raloxifene on the incidence of invasive breast cancer in postmenopausal women with osteoporosis categorized by breast cancer risk.

PURPOSE: To assess the effect of raloxifene, indicated for osteoporosis treatment and prevention, on invasive breast cancer in subgroups of postmenopausal women defined by risk factors for breast cancer. EXPERIMENTAL DESIGN: Data from the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial (N=7,705) and a follow-up study, the 4-year Continuing Outcomes Relevant to Evista (CORE) trial (N=4,011), were analyzed. Prespecified subgroups were defined by age (>or=65 versus<65 years), age at menopause (>or=49 versus<49 years), body mass index (>or=25 versus<25 kg/m2), family history of breast cancer (yes/no), serum estradiol level (5-10 versus<5, >10 versus<5 pmol/L), prior estrogen therapy (yes/no), and bone mass at MORE baseline, and 5-year predicted risk, assessed using the modified Gail model (>or=1.67 versus<1.67%), at CORE baseline. Time-to-first invasive breast cancer was analyzed using Cox proportional hazards models. RESULTS: In the placebo group, older age, higher estradiol level, and a family history of breast cancer were associated with an increased breast cancer risk (P<0.05). Raloxifene therapy was associated with a reduced breast cancer risk in both women at lower and those at higher breast cancer risk. Hazard ratio point estimates were 0.11 to 0.67, corresponding to a 33% to 89% reduction in breast cancer risk with raloxifene versus placebo. The therapy by family history interaction was significant (P=0.04). CONCLUSIONS: Raloxifene therapy was associated with a reduced risk of invasive breast cancer in postmenopausal women irrespective of the presence/absence of risk factors; its effect was greater in women with a family history of breast cancer.

Safety assessment of raloxifene over eight years in a clinical trial setting.

OBJECTIVE: Osteoporosis is a chronic disorder that warrants long-term therapy. If benefits are to outweigh risks, the long-term safety profiles of these therapies must be favorable. The aim of this study was to assess the safety of raloxifene over 8 years in 4011 postmenopausal women with osteoporosis in a clinical trial setting through adverse event reporting. METHODS: Data analyzed comprised all reported adverse events collected at each visit of both the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, and the subsequent Continuing Outcomes Relevant to Evista (CORE) trial. MORE was an international, 4-year double-blind, randomized, placebo-controlled study, designed to assess the effect of raloxifene on bone mineral density and vertebral fracture incidence in 7705 (placebo, 2576; raloxifene, 5129) postmenopausal women with osteoporosis. Breast cancer was a secondary endpoint. Based on the breast cancer findings of MORE, the CORE trial, a 4-year double-blind, placebo-controlled trial of a subset of MORE participants, was subsequently conducted. CORE enrolled 4011 (placebo, 1286; raloxifene, 2725) participants and was designed to examine raloxifene's effect on breast cancer incidence. Safety analyses were performed using the intention-to-treat principle, and comparison between therapies was analyzed using a two-sided Fisher's exact test. RESULTS: Over the 8 years of follow-up of 4011 women, there was no difference in all-cause mortality or hospitalization incidence between raloxifene and placebo groups (p > 0.1). Excluding breast cancer and non-melanoma skin cancer, cancer incidence was 4.6% and 6.3% in the raloxifene and placebo group, respectively (p = 0.027). Raloxifene was associated with a 1.7-fold increase in venous thromboembolism incidence (95% confidence interval 0.93-3.14), with an absolute risk difference of 0.9 per 1000 woman-years. There was no difference in the incidence of myocardial infarction, stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups (p > 0.5). Uterine polyps, hot flushes and muscle cramps were more common in those receiving raloxifene versus placebo (p = 0.028, p < 0.001, and p = 0.008, respectively). CONCLUSION: These 8-year data support the known clinical safety profile of raloxifene, established in the MORE trial.

Association of leptin with poor ovarian stimulation during in vitro fertilization.

OBJECTIVE: To evaluate whether serum leptin levels are predictive of in vitrofertilization (IVF) outcome. STUDY DESIGN: A nested, case-control study was performed on patients undergo-formed on patients undergoing IVF. Ovarian stimulation was performed with a set protocol. At the conclusion of the stimulation, patients were divided into 2 groups, poor stimulator (PS) and high stimulator (HS), based on the number of follicles seen on ultrasound. The PS group contained patients with < 12 follicles > 13 mm in diameter; the HS group contained patients with > or = 12 follicles > 13 mm. Blood from the start of the cycle in which human chorionic gonadotropin (hCG) was administered was assayed for leptin and estradiol. The number of follicles obtained, number of oocytes retrieved, quality of the oocytes and quality of the embryos were calculated. Mean leptin and estradiol levels were compared using Student's t test. Pearson correlation coefficients were calculated to assess the relationship between leptin and the other outcome variables. RESULTS: Mean leptin levels (+/- SEM) at the start of the cycle (21.5 +/- 2.9 ng/dL for PS and 34.6 +/- 14.0 ng/dL for HS) and on the day of hCG (53.2 +/- 5.37 ng/dL for PS and 50.4 +/- 9.1 ng/dL for HS) were not significantly different. CONCLUSION: Leptin levels obtained at the start of stimulation or on the day of hCG administration are not predictive of IVF outcome.

Compliance with mammography and bone mineral density screening in women at least 50 years old.

OBJECTIVE: The aim of this study was to examine the utilization of mammography and bone mineral density (BMD) screenings and factors associated with compliance according to the recommended clinical practice guidelines. METHODS: Mammography and BMD were assessed using employer's administrative claims data for eligible women identified between January 2004 and December 2006. Women were categorized into five cohorts based on mammography- and BMD-recommended screening guidelines. Logistic regression modeling was used to examine the covariates associated with compliance. RESULTS: Mammography and BMD screening utilization were low in relation to recommendations, with 21%, 27%, and 16% of women complying with mammography, age-motivated BMD, and fracture-motivated BMD screening guidelines, respectively. BMD screening use (odds ratio [OR], 7.19; 95% CI, 7.08-7.31) was associated with compliance in the mammogram cohort. Mammogram use was associated with compliance in both the age-motivated BMD cohort (OR, 6.01; 95% CI, 5.28-6.85) and the fracture-motivated BMD cohort (OR, 2.20; 95% CI, 2.07-2.33). Having a Papanicolaou test was strongly associated with compliance in the combined mammogram plus age-motivated BMD cohort (OR, 16.83; 95% CI, 14.01-20.22) and the combined mammogram plus fracture-motivated BMD cohort (OR, 10.46; 95% CI 9.26-11.81). CONCLUSIONS: Postmenopausal women with employer-sponsored health insurance had low utilization of mammography and BMD screening relative to clinical guidelines. Use of other health screening services was associated with compliance with guidelines. Methods to improve adherence to mammography and BMD screening guidelines should be explored, which could possibly leverage the increased likelihood that women who receive one screening service will receive another.

Patient characteristics and utilization of breast cancer screening or diagnostic procedures prior to initiation of raloxifene, bisphosphonates and calcitonin.

OBJECTIVE: This study evaluated the characteristics of postmenopausal women who initiated on raloxifene, bisphosphonates, and calcitonin, specifically evaluating the use of breast cancer screening or diagnostic procedures prior to initiation of therapy. RESEARCH DESIGN AND METHODS: Women 50 years and older with at least one claim for raloxifene (RLX), bisphosphonates (BIS), or calcitonin (CT) in 2005 or 2006 and continuous enrollment (with consecutive gaps in enrollment of no more than 1 month) from January 2004 to December 2007 were identified in a large national commercial and Medicare claims database. Treatment-naïve postmenopausal women initiating on raloxifene, bisphosphonates, and calcitonin were compared in terms of breast cancer screening or diagnostic procedures (i.e., mammogram, breast MRI, ultrasound, and biopsy) as well as age, provider specialty, fractures, bone mineral density screening, Chronic Disease Scores, and comorbidities. RESULTS: Treatment-naïve patients initiated on raloxifene were younger than those initiated on bisphosphonates and calcitonin (mean age 63 years [RLX], 66 years [BIS], 72 years [CT]; p < 0.05). Treatment-naïve patients initiated on raloxifene were more likely to have had breast cancer screening or diagnostic procedures in the 12 months prior to therapy initiation than treatment-naïve bisphosphonate or calcitonin patients (RLX 61%, BIS 57%, CT 41%; p < 0.05), and were more likely to have an increased frequency of mammograms in the 12 months after therapy initiation (RLX 18%, BIS 16%, CT 15%; p < 0.05). Calcitonin patients were the most likely to have had a fracture in the pre-period followed by bisphosphonates then raloxifene patients. CONCLUSION: These data suggest that there are differences in the clinical characteristics of postmenopausal women who initiate osteoporosis medications specifically in regards to age, pre-period fractures and breast cancer screening or diagnostic procedure use prior to initiation. Key limitations include general claims database limitations, lack of ability to assess behavior change, and lack of information on therapy initiation rationale.

Raloxifene use in clinical practice: efficacy and safety.

OBJECTIVE AND METHODS: In this article, we provide an interdisciplinary concise review of the effects of raloxifene on breast, bone, and reproductive organs, as well as the adverse events that may be associated with its use. RESULTS: Raloxifene has been shown to prevent osteoporosis in postmenopausal women (PMW) with low bone mass and prevent vertebral fractures in those with osteoporosis/low bone mass; it has not been shown to reduce the risk of nonvertebral fractures. Raloxifene reduces the risk of invasive breast cancer in PMW with osteoporosis or at high risk of breast cancer. The risk of venous thromboembolism has been consistently shown to be increased with raloxifene, so it should not be used in women at high risk of venous thromboembolism. Although raloxifene does not increase, nor decrease, the risk of coronary or stroke events overall, in the raloxifene trial of PMW at increased risk of coronary events, the incidence of fatal stroke was higher in women assigned raloxifene versus placebo. CONCLUSIONS: Based on its approved indications, it is appropriate to prescribe raloxifene to prevent or treat osteoporosis, as well as to reduce the risk of invasive breast cancer in PMW with osteoporosis or at high risk of breast cancer. Women at increased risk of both fracture and invasive breast cancer are those most likely to receive a dual benefit with raloxifene. Decision making must involve the incorporation of the woman's personal feelings about the risks and benefits of raloxifene therapy, balanced with her interest in reducing risk of fractures and breast cancer through pharmacological intervention.

Relationship between bone mass, invasive breast cancer incidence and raloxifene therapy in postmenopausal women with low bone mass or osteoporosis.

OBJECTIVE: To evaluate the relationship between bone mass and risk of breast cancer and to determine the effect of raloxifene therapy on breast cancer incidence in women categorized by bone mass into low bone mass and osteoporosis subgroups. DESIGN: In this post hoc analysis, data were analyzed from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, enrolling postmenopausal women with low bone mass (N = 7705), and the Continuing Outcomes Relevant to Evista (CORE) trial, a follow-up to MORE enrolling 4011 MORE participants. Total follow-up was for up to 8 years. Women with a total hip bone mineral density (BMD) T-score < -1 to > -2.5 or T-score < or = -2.5 (referent, NHANES III database) were classified as having low bone mass or osteoporosis, respectively. Women with a pre-existing vertebral fracture were considered as having osteoporosis irrespective of BMD T-score. Analyses were performed for invasive breast cancers and invasive estrogen-receptor (ER) positive breast cancers. RESULTS: Women with low bone mass (N = 3829) had a twofold higher incidence of invasive ER-positive breast cancer than those with osteoporosis (N = 3836) (HR 2.13, 95% CI 1.12-4.03). The incidence of all invasive breast cancers did not differ significantly between the bone mass groups. The incidences of invasive and invasive ER-positive breast cancers were 65-78% lower in women assigned raloxifene versus placebo in both the low bone mass and osteoporosis groups (p < 0.05). CONCLUSIONS: In this post hoc analysis of postmenopausal women participating in MORE and CORE, bone mass was a predictor of invasive ER-positive breast cancer. Raloxifene treatment reduced the risk of invasive and invasive ER-positive breast cancers in women with low bone mass and those with osteoporosis. Since participants were older postmenopausal women with low bone mass, whether these findings can be generalized to other postmenopausal women is unclear.

Risk factors for breast cancer in older women: the relative contribution of bone mineral density and other established risk factors.

AIM: To determine the contribution of bone mineral density (BMD) to breast cancer risk relative to other established breast cancer risk factors in postmenopausal women with osteoporosis. METHODS: Data for this analysis comprised those collected from women randomized to placebo in the MORE and CORE trials (N = 2,576). Risk factors measured at baseline included age, family history of breast cancer, estradiol level, body mass index, prior hormone therapy, BMD and vertebral fracture status. Cox proportional hazards regression models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over a total of 13,698 woman-years of follow-up, 65 incident breast cancers occurred. In univariate analyses, older age and family history of breast cancer were the strongest predictors of breast cancer risk, associated with a 2.4- and 2.6-fold increase in breast cancer incidence. A higher estradiol level was associated with a 1.9-fold increase in breast cancer incidence. The association between femoral neck BMD and breast cancer incidence was only significant after adjustment for age (P = 0.03). The final multivariable model included age, family history, estradiol, BMD, and the BMD-estradiol interaction since the effect of BMD on breast cancer varied by estradiol level (interaction P-value, 0.04); in those with a lower estradiol level, a higher BMD was associated with a 2.6-fold increased in breast cancer. CONCLUSION: Overall, BMD is a relatively weak predictor of breast cancer risk in these postmenopausal women with osteoporosis, after taking into consideration age, family history and endogenous estradiol level.

Hemodynamic effects of acute and repeated exposure to raloxifene in ovariectomized sheep.

We hypothesize that administration of acute and daily doses of raloxifene will have significant effects on ovine coronary and uterine hemodynamics and that these changes are estrogen receptor dependent. Eleven ovariectomized sheep were instrumented to measure mean arterial pressure, heart rate (HR), cardiac output (CO), and coronary (CBF) and uterine artery blood flows (UBF). A dose-response curve was generated for raloxifene (1, 3, and 10 microg/kg) and compared with a standard dose of estradiol-17beta (1 microg/kg) given intravenously. In a second group of animals, raloxifene (10 microg.kg-1.day-1) was administered intravenously for 14 consecutive days, and cardiovascular responses were compared with a group of animals administered estradiol-17beta (10 microg/kg) daily for the same period. To determine whether raloxifene-related vascular responses were estrogen receptor (ER) mediated, the animals were pretreated with estrogen antagonist ICI-182,780 given intravenously. Finally, RT-PCR was preformed to determine the presence of ERalpha and ERbeta mRNA in ovine coronary and uterine vessels. Raloxifene increased CBF and UBF dose dependently with a parallel decrease in the associated vascular resistances. Acute cardiovascular responses to daily doses of raloxifene and estradiol-17beta were sustainable. In contrast to estradiol-17beta, which significantly increases CO by increasing HR but not stroke volume, raloxifene significantly increased stroke volume without a significant parallel increase in HR. ICI-182,780 abolished raloxifene-induced hemodynamic responses, and ERalpha and ERbeta mRNA are present in both ovine coronary and uterine vessels. Hence, the hemodynamic effects of raloxifene are dose dependent, sustainable, and estrogen receptor mediated.

Estrogen increases inducible nitric oxide synthase gene expression.

OBJECTIVE: The goal of this study was to determine whether estrogen increases the expression of the inducible nitric oxide synthase gene. STUDY DESIGN: An inducible nitric oxide synthase fusion gene was created with its promoter and the reporter gene, luciferase. COS cells were transfected transiently with the fusion gene and cotransfected with an estrogen receptor-alpha expression plasmid to ensure the presence of an estrogen receptor. Cells were then exposed to estradiol (1 nmol/L and 10 nmol/L) or a cytokine mix that consisting of tumor necrosis factor-alpha, interleukin-1beta, and interferon gamma. Gene expression was measured in relative light units. RESULTS: Estradiol increased the expression of inducible nitric oxide synthase by an average of 31.2% in the COS cells that were cotransfected with estrogen receptor compared with -10.4% in cells without estrogen receptor (P =.006). CONCLUSION: Inducible nitric oxide synthase expression was increased with the addition of estrogen. These data support previous studies that demonstrated the inflammatory effects of estrogen and provides further insight into the mechanism by which estrogen might have an impact on the cardiovascular system.

Estrogen increases iNOS expression in the ovine coronary artery.

Estrogen is believed to protect postmenopausal women from coronary vascular disease, in part by increasing production of nitric oxide (NO). In this study, we investigated the possibility that transcriptional activation of inducible NO synthase (iNOS) is responsible for a component of the estrogen-induced increase in coronary blood flow. Twenty-two ewes were instrumented with Doppler flow probes on their left circumflex coronary and pulmonary arteries. Nine ewes received 17beta-estradiol (1 microg/kg), and the coronary vascular response was followed for 16 h. Estradiol significantly increased coronary blood flow by 22 +/- 4% over baseline and the peak response occurred at 2 h (P < 0.01). To examine the effect of estrogen on NOS expression in the ovine coronary artery, 17 noninstrumented animals were killed 2 h after administration of estradiol or vehicle. Coronary arteries were analyzed for ovine iNOS and endothelial NOS (eNOS) expression by semiquantitative RT-PCR. PCR primers were based on partial cDNA clones for ovine eNOS and iNOS isolated as part of this study. The expression of iNOS was significantly increased (27-fold) by the administration of estradiol, whereas the expression of eNOS was much weaker (2-fold). To confirm these effects in vivo, additional instrumented animals received either the estrogen receptor (ER) antagonist ICI-182,780 (n = 5), the iNOS antagonist dexamethasone (n = 5), or pyrrolidine dithiocarbamic acid, an inhibitor of nuclear factor-kappaB (n = 5). All three antagonists inhibited estrogen-induced increases in coronary blood flow and increases in cardiac output by over 85%. These results strongly support the hypothesis that 17beta-estradiol increases coronary blood flow in the unanesthetized nonpregnant ewe via an ER-dependent mechanism that results in an increase in both eNOS and iNOS expression.

Differential effects of selective estrogen receptor modulators and estrogens on mammary blood flow in the ovine.

OBJECTIVE: Hormone replacement therapy has been implicated in the increased incidence of breast cancer, although selective estrogen receptor modulators have been shown to be effective in the prevention of breast cancer. Breast cancers are associated with increased mammary blood flow compared to benign breast lesions. However, few studies have examined the hemodynamic effects of hormonal agents on the mammary circulation that promote or reduce the risk of breast cancers. Although estradiol-17beta has been shown to increase mammary blood flow, the effect of selective estrogen receptor modulators remains undetermined. We therefore compared the vascular effects of selective estrogen receptor modulators and estrogens on mammary blood flow. STUDY DESIGN: Fourteen nonpregnant ovariectomized ewes were instrumented to measure mean arterial pressure, heart rate, and uterine and mammary blood flows. Compounds were administered intravenously on separate days, and responses were monitored up to 4 hours. Compounds that were studied included estradiol-17beta (1 microg/kg), conjugated equine estrogens (0.625 and 1.25 mg), tibolone (2.5 and 5 mg), raloxifene (10 microg/kg), and tamoxifen (300 microg/kg). RESULTS: None of these compounds significantly affected mean arterial pressure or heart rate, but all of the compounds significantly increased uterine blood flow. Estradiol-17beta increased mammary blood flow by 98% +/- 25%; conjugated equine estrogen increased mammary blood flow by 46% +/- 6% and 68% +/- 13% at the 0.625 and 1.25 mg doses, respectively. Tibolone increased mammary blood flow by 37% +/- 13% at the 2.5-mg dose and by only 14% +/- 4% at the 5-mg dose. Neither raloxifene nor tamoxifen significantly altered mammary blood flow. CONCLUSION: Although estrogens and selective estrogen receptor modulators induced similar increases in uterine blood flow, they had differential effects on mammary blood flow.