Ribociclib Plus Letrozole in Patients with Hormone Receptor-positive,HER2-negative Advanced Breast Cancer with No Prior Endocrine Therapy: Subgroup Safety Analysis from The Phase 3b CompLEEment-1 Trial

BackgroundThe CDK4/6 inhibitor, ribociclib in combination with endocrine therapy significantly improved progression-free survival in the first line setting in post-menopausal patients with HR+/HER2− advanced breast cancer (ABC) in a pivotal phase 3, placebo-controlled trial (MONALEESA-2) and demonstrated superior overall survival in premenopausal patients with HR+/HER2− ABC (MONALEESA-7). The multinational, phase 3b, CompLEEment-1 trial, which assessed the safety and efficacy of ribociclib plus letrozole in a broader population of patients who have not received prior endocrine therapy for advanced disease, is the largest phase 3 clinical trial to date to evaluate the safety and efficacy of a CDK4/6 inhibitor. We report a subanalysis of data from patients (N = 339) enrolled in the central and south European countries of the SERCE (Southern Europe, RUC, Central Europe) cluster of CompLEEment-1.Patients and methodsMen and women of any menopausal status with HR+/HER2− ABC received once-daily oral ribociclib 600 mg (3-weeks on/1-week-off), plus letrozole 2.5 mg continuously. Men/premenopausal women also received a GnRH-agonist. The primary outcome was the number of patients with adverse events (AEs) over a timeframe of approximately 36 months. Time-to-progression, overall response rate, and clinical benefit rate were also measured.ResultsSafety results in the SERCE subgroup were consistent with those in the pivotal clinical trials of ribociclib in combination with endocrine therapy. Treatment-related AEs leading to dose adjustments/interruption occurred in 63.1% of patients but led to treatment discontinuation in only 10.6%. The most common treatment-related AEs of grade ≥ 3 were neutropenia and transaminase elevations. There were no fatal treatment-related events.ConclusionsThese findings from the SERCE subgroup support the safety and manageable tolerability of ribociclib in a broad range of patients with HR+/HER2− ABC more representative of patients in real-world clinical practice.Key words: CDK4/6 inhibitor, ribociclib, HR+, HER2−, advanced breast cancer, CompLEEment-1 trial     

Treatment of hyperparathyroidism with cinacalcet in kidney transplant recipients

Background

After successful kidney transplantation, hyperparathyroidism can persist in 10%–50% of patients and can harmfully affect bone metabolism. Calcimimetic cinacalcet is a new treatment option in the management of persistent hyperparathyroidism in these patients.

Methods

This prospective, clinical study of 11 patients included those who had a serum intact parathyroid hormone (iPTH) concentration >65 ng/L, a serum creatinine concentration was <200 μmol/L, stable kidney graft function, and were >1 year since transplantation. Patients were not treated with drugs other than calcitriol that could influence bone metabolism. During the 6-month observation period, in which the stability of measured parameters was determined, and in the 12-month treatment period (cinacalcet 30 mg/d), we followed serum concentrations of calcium, phosphate, iPTH, creatinine, vitamin 25OH D₃, bone-specific alkaline phosphatase (ALP), osteocalcin, collagen degradation fragments (CTX), urinary calcium excretion, and bone mineral density (BMD).

Results

During the treatment period, the serum calcium concentration decreased significantly (from 2.50 ± 0.12 to 2.32 ± 0.12 mmol/L; P < .01). Serum iPTH concentration decreased significantly (from 247 [range, 199–362] at time 0 to 198 [range, 165–233] ng/L after 1 month of treatment; P < .05), but increased slightly thereafter. After 6 months of treatment, the serum concentration of ALP and CTX increased significantly, but decreased thereafter. There were no significant changes in the other parameters assessed. Renal function remained stable during the treatment period. The BMD of the lumbar spine, hip, and forearm did not change during the 12 months of treatment.

Conclusion

Cinacalcet was effective in treating posttransplant hyperparathyroidism, resulting in decreased calcemia and transient decreased iPTH. ALP and CTX transiently increased during therapy, but other markers of bone metabolism remained unchanged. Twelve months of cinacalcet treatment did not result in a change in BMD. Cinacalcet seems to be a safe drug with no negative effect on renal function.     

Pooled analysis of prognostic impact of uPA and PAI-1 in breast cancer patients

In this report we present an extension of the pooled analysis of the prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I in breast cancer patients. We analyzed a different endpoint, metastasis-free survival (MFS). We checked the consistency of the estimates for uPA and PAI-1 for relapse-free survival (RFS) and MFS exploring possible sources of heterogeneity. Nodal status, the most important prognostic factor for breast cancer, introduced heterogeneity in the uPA/PAI-1 survival analyses, reflecting the interaction between nodal status and uPA/PAI-1. The estimates for uPA and PAI-1 were found to be consistent, even when a different transformation of their values was used. The heterogeneity of the separate data sets decreased if the levels of uPA and PAI-1 were ranked, data sets were pooled, and the analyses corrected for the base model that included all traditional prognostic factors, and stratified by data set. We conclude that uPA and PAI-1 are ready to be used in the clinic to help classify breast cancer patients into high and low risk groups.     

Pharmacoeconomic aspects of adjuvant anastrozole or tamoxifen in breast cancer: a Slovenian perspective

New treatment approaches that include the use of aromatase inhibitors in adjuvant breast cancer management are associated with higher efficacy and increased drug costs. Our aim was to calculate the difference in total costs of care associated with two therapeutic options, anastrozole and tamoxifen, from the perspective of a healthcare provider. The cost of care and a decision tree analysis were used in this assessment. The efficacy of both drugs in terms of relapse rate was obtained from an ATAC (Arimidex, Tamoxifen Alone or in Combination) trial after the median observational time of 68 months. The total sum of all direct healthcare costs over a 60-month period was 14,438 and 8,009 Euros per person in the anastrozole and tamoxifen arm, respectively. Despite higher total costs of care associated with anastrozole, the drug cost ratio of anastrozole/tamoxifen=8.1/1 converted to a ratio of only 1.75/1 in favor of tamoxifen when costs of recurrence and adverse events were included. The total costs of care, including disease recurrences and adverse event management obtained in our analysis were similar to total costs of care values for other surveys, which lead us to believe that anastrozole is also a cost-effective alternative to tamoxifen in Slovenia.     

Cellular Polyamines Promote Amyloid-Beta (Aβ) Peptide Fibrillation and Modulate the Aggregation Pathways

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3,4-Dihydro-2H-1,4-benzoxazine derivatives combining thrombin inhibitory and glycoprotein IIb/IIIa receptor antagonistic activity as a novel class of antithrombotic compounds with dual function

3,4-Dihydro-2 H-1,4-benzoxazine derivatives possessing both thrombin inhibitory and glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonistic activities were obtained by combining mimetics of the d-Phe-Pro-Arg pharmacophore of thrombin inhibitors and the Arg-Gly-Asp pharmacophore of GPIIb/IIIa receptor antagonists in the same low molecular weight peptidomimetic compound. Systematic variation of the position of substituents around the 3,4-dihydro- 2H-1,4-benzoxazine nucleus, the distance between the carboxylate and amidine moieties, together with additional substituents to fill the thrombin S 2 and S 3 pockets resulted in compounds displaying submicromolar inhibition constants ( K i) for thrombin and submicromolar IC 50 for inhibition of binding of fibrinogen to platelet GPIIb/IIIa receptor. Some of these compounds, such as 17a, 17b, 17d, and 17h possessing a well balanced activity at both targets, are a good starting point for further optimization. Incorporation of anticoagulant and platelet antiaggregatory activity in the same molecule constitutes a promising approach toward novel antithrombotic agents.     

Effect of the multidrug resistance modulator valspodar on serum cortisol levels in rabbits

Purpose: To contribute to a better understanding of the physiological role of P-glycoprotein (P-gp) in the adrenal gland, we initiated our studies in rabbits. The aim of our study was to explore the effect of the selective multidrug resistance (MDR) modulator PSC 833 (valspodar) on serum cortisol in rabbits. Methods: Baseline and corticotropin-stimulated serum cortisol levels were measured before and after valspodar treatment in adult male rabbits. Seven rabbits were treated with 50 mg/kg per dose and seven, with 75 mg/kg per dose of valspodar subcutaneously. Serum cortisol levels were determined by radioimmunoassay adjusted for expected values. Results: Serum cortisol levels (baseline as well as corticotropin-stimulated) increased after both valspodar treatment regimens. The increase was dose-dependent and was higher for the baseline than for the corticotropin-stimulated values. Serum valspodar levels exceeding 1000 ng/ml were achieved in all except one animal in each group. We hypothesize that the increased serum cortisol levels were due to increased adrenocorticotropic hormone (ACTH) secretion after valspodar treatment, but, unfortunately, we could not measure ACTH properly in rabbits by means of the commercially available kits. Conclusions: Our study indicates that P-gp is not involved in steroid hormone secretion in the adrenal gland. This is evident from observations that serum cortisol levels were found to have increased rather than decreased in rabbits treated with a P-gp blocker and that the treated animals appeared healthy and normal. Since P-gp was found to play an important role in protection against xenobiotics in some other organs, further studies to explore the protective role of P-gp in the adrenal gland are warranted. Received: 2 September 1997 / Accepted: 28 October 1997     

Prognostic value of the urokinase-type plasminogen activator,and its inhibitors and receptor in breast cancer patients

Urokinase-type plasminogen activator (uPA), its inhibitors (PAI-1 and PAI-2), and its receptor (uPAR) play a key role in tumor invasion and metastasis. This study was designed to evaluate the prognostic impact of uPA, PAI-1, PAI-2, and uPAR and the combination of these factors in a group of 460 primary breast cancer patients. Concentrations of all 4 components of the uPA system were measured in tumor extracts using enzyme-linked immunosorbent assays (American Diagnostica, Inc, Greenwich, CT). After a median follow-up of 33 months, 18.5% of the patients had relapsed. The Cox proportional hazards model was applied for both univariate and multivariate analyses of disease-free survival (DFS). PAI-1 and PAI-2 were shown to provide independent prognostic information in breast cancer. Patients with either low levels of PAI-1 or high levels of PAI-2 were found to have better DFS (relative risk was 2.08 and 1.78, respectively). The prognostic value could be even further improved by a combination of both inhibitors. Aside from the uPA inhibitors, only nodal status and hormonal receptor status retained independent prognostic value. The other 2 invasion markers, uPA and uPAR, showed no statistically significant impact on DFS. In our patients, who were mostly treated with adjuvant therapy, uPA was not found to be an independent prognostic marker for DFS; this could be a consequence of the predictive value of uPA for response to adjuvant therapy and should be further investigated.     

Prognostic and predictive value of cathepsins D and L in operable breast cancer patients

None of the established prognostic factors in breast cancer (BC) is able to determine the final outcome with certainity. Tumor biological factors involved in tumor invasion and metastasis, such as cathepsins and proteins of u-PA system, have been put forward in the recent literature as strong novel prognostic factors in BC. We therefore evaluated prognostic and predictive value of cathepsin-D (CD) and cathepsin-L (CL) in 715 operable BC patients. CD and CL were determined in tumor extracts using immunoradiometric and ELISA assays, respectively. During follow-up (median 37 months), 151 (21%) patients relapsed. In a multivariate analysis of disease-free survival (DFS), CL (p=0.04), nodal status (p<0.001) and hormone receptor status (p<0.001) were the only independent significant prognostic factors. CL thus provided independent prognostic information on DFS and could also predict a response to adjuvant chemotherapy (ChT), while CD had no significant prognostic and predictive impact.