Purpose This phase III study evaluated ribociclib plus fulvestrant in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who were treatment naïve or had received up to one line of prior endocrine therapy in the advanced setting. Patients and Methods Patients were randomly assigned at a two-to-one ratio to ribociclib plus fulvestrant or placebo plus fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. Results A total of 484 postmenopausal women were randomly assigned to ribociclib plus fulvestrant, and 242 were assigned to placebo plus fulvestrant. Median progression-free survival was significantly improved with ribociclib plus fulvestrant versus placebo plus fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consistent treatment effects were observed in patients who were treatment naïve in the advanced setting (hazard ratio, 0.577; 95% CI, 0.415 to 0.802), as well as in patients who had received up to one line of prior endocrine therapy for advanced disease (hazard ratio, 0.565; 95% CI, 0.428 to 0.744). Among patients with measurable disease, the overall response rate was 40.9% for the ribociclib plus fulvestrant arm and 28.7% for placebo plus fulvestrant. Grade 3 adverse events reported in ≥ 10% of patients in either arm (ribociclib plus fulvestrant v placebo plus fulvestrant) were neutropenia (46.6% v 0%) and leukopenia (13.5% v 0%); the only grade 4 event reported in ≥ 5% of patients was neutropenia (6.8% v 0%). Conclusion Ribociclib plus fulvestrant might represent a new first- or second-line treatment option in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.
- MeSH
- aminopyridiny aplikace a dávkování škodlivé účinky MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- fulvestrant aplikace a dávkování škodlivé účinky MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu farmakoterapie mortalita MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- puriny aplikace a dávkování škodlivé účinky MeSH
- receptor erbB-2 biosyntéza MeSH
- receptory pro estrogeny biosyntéza MeSH
- receptory progesteronu biosyntéza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: Breast cancer is the most common malignancy with the highest incidence rates among women worldwide. Triple-negative breast cancer (TNBC) represents the major phenotype of basal-like molecular subtype of breast cancer, characterized by higher incidence in young women and a very poor prognosis. MicroRNAs (miRNAs) are small non-coding RNAs playing significant role in the pathogenesis of many cancers including breast cancer. Therefore, miRNAs are also potential prognostic and/or predictive biomarkers in triple-negative breast cancer patients. METHODS: Thirty-nine TNBC patients with available formalin-fixed paraffin-embedded (FFPE) tissues were enrolled in the study. MiR-34a, miR-34b, and miR-34c were analyzed using qRT-PCR and correlated to clinico-pathological features of TNBC patients. RESULTS: Expression levels of miR-34b significantly correlate with disease free survival (DFS) (p = 0.0020, log-rank test) and overall survival (OS) (p = 0.0008, log-rank test) of TNBC patients. No other significant associations between miR-34a, miR-34b, and miR-34c with available clinical pathological data were observed. CONCLUSIONS: MiR-34b expression negatively correlates with disease free survival and overall survival in TNBC patients. Thus, miR-34b may present a new promising prognostic biomarker in TNBC patients, but independent validations are necessary.
- MeSH
- dospělí MeSH
- Kaplanův-Meierův odhad MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA analýza genetika MeSH
- nádorové biomarkery genetika MeSH
- nádory prsu genetika mortalita patologie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- přežití po terapii bez příznaků nemoci MeSH
- prognóza MeSH
- proporcionální rizikové modely MeSH
- receptor erbB-2 biosyntéza genetika MeSH
- receptory pro estrogeny biosyntéza genetika MeSH
- receptory progesteronu biosyntéza genetika MeSH
- regulace genové exprese u nádorů MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Gene expression microarrays are being used to develop new prognostic and predictive tests for breast cancer, and might be used at the same time to confirm oestrogen-receptor status and ERBB2 status. Our goal was to establish a new method to assign oestrogen receptor and ERBB2-receptor status to breast carcinoma based on mRNA expression measured using Affymetrix U133A gene-expression profiling. METHODS: We used gene expression data of 495 breast cancer samples to assess the correlation between oestrogen receptor (ESR1) and ERBB2 mRNA and clinical status of these genes (as established by immunohistochemical [IHC] or fluorescence in-situ hybridisation [FISH], or both). Data from 195 fine-needle aspiration (FNA) samples were used to define mRNA cutoff values that assign receptor status. We assessed the accuracy of these cutoffs in two independent datasets: 123 FNA samples and 177 tissue samples (ie, resected or core-needle biopsied tissues). Profiling was done at two institutions by use of the same platform (Affymetrix U133A GeneChip). All data were uniformly normalised with dCHIP software. FINDINGS: ESR1 and ERBB2 mRNA levels correlated closely with routine measurements for receptor status in all three datasets. Spearman's correlation coefficients ranged from 0.62 to 0.77. An ESR1 mRNA cutoff value of 500 identified oestrogen-receptor-positive status with an overall accuracy of 90% (training set), 88% (first validation set), and 96% (second validation set). An ERBB2 mRNA threshold of 1150 identified ERBB2-positive status with the overall accuracy of 93% (training set), 89% (first validation set), and 90% (second validation set). Reproducibility of mRNA measurements in 34 replicate experiments was high (correlation coefficient 0.975 for ESR1, 0.984 for ERBB2). INTERPRETATION: Amounts of ESR1 and ERBB2 mRNA as measured by the Affymetrix GeneChip reliably and reproducibly establish oestrogen-receptor status and ERBB2 status, respectively.
Triple-negative breast cancers are defined by a lack of expression of oestrogen, progesterone, and ERBB2 receptors. This subgroup accounts for 15% of all types of breast cancer and for a higher percentage of breast cancer arising in African and African-American women who are premenopausal. Because of the absence of specific treatment guidelines for this subgroup, triple-negative breast cancers are managed with standard treatment; however, such treatment leaves them associated with a high rate of local and systemic relapse. Histologically, such cancers are poorly differentiated, and most fall into the basal subgroup of breast cancers, characterised by staining for basal markers (ie, cytokeratin 5/6). Analyses of microarray gene-expression profiling data show that they form a homogeneous group (or so-called cluster) in transcriptional terms and, increasingly, research studies are identifying basal cancers on the basis of exhibiting this distinctive transcriptional profile. Histologically and transcriptionally, triple-negative breast cancers have many similarities to BRCA1-associated breast cancers, which suggests that dysfunction in BRCA1 or related pathways occurs in this subset of sporadic cancers. In this review, we discuss the molecular features of triple-negative breast cancers and consider how the use of existing cytotoxic agents can be optimised for this patient group. We discuss the implications of a possible underlying BRCA1-pathway dysfunction in this subgroup in terms of treatment and we also investigate the predominant proliferative signals and the on-going research addressing the suitability of these signals as therapeutic targets.
Determination of chemosensitivity/chemoresistance is becoming increasingly important for individualization of breast cancer chemotherapy. We developed a simple non-destructive test of cellular activity (NTCA) for assessment of the cytopathic effect of antitumour drugs in vitro. Contrary to routinely used methods (e.g. MTT), besides the comparative evaluation of metabolic activity using pH (given by the medium colour), the NTCA enables the simultaneous assessment of proliferation and morphology of cultured cells (phase-contrast microscopy) at any time during the incubation with cytostatics. Moreover, the regenerative potential of the cells can be examined by cell recovery and growth after drug removal. We provide evidence for the relevance of NTCA in chemosensitivity testing of primary breast cancer cells and breast cancer cell lines for cisplatin, gemcitabine and tamoxifen. NTCA represents a simple addition to the chemosensitivity assessment and could also serve for rapid screening of new antitumour strategies.
- MeSH
- antitumorózní látky farmakologie MeSH
- buněčné linie MeSH
- buňky - růstové procesy účinky léků MeSH
- cisplatina aplikace a dávkování MeSH
- deoxycytidin aplikace a dávkování farmakologie MeSH
- financování organizované MeSH
- léky antitumorózní - screeningové testy metody MeSH
- lidé MeSH
- mléčné žlázy lidské cytologie účinky léků MeSH
- nádorové buněčné linie MeSH
- nádory prsu farmakoterapie metabolismus patologie MeSH
- protokoly antitumorózní kombinované chemoterapie farmakologie MeSH
- receptory pro estrogeny biosyntéza MeSH
- reprodukovatelnost výsledků MeSH
- tamoxifen aplikace a dávkování MeSH
- tetrazoliové soli MeSH
- thiazoly MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
In this study we present results of investigations of progesterone and estrogen receptors in most frequent, WHO grade I histological types of meningiomas (meningothelial, fibrous, and transitional) and in atypical--WHO grade II variant of these tumors. Samples from 64 tumors were examined. The cohort consisted of 46 WHO grade I (21 transitional, 13 fibrous and 12 meningothelial histologic variants) and of 18 atypical meningiomas. Apart from immunohistochemical examination of progesterone and estrogen receptors, MIB 1 labeling index was estimated. Positive immunoreaction for progesterone receptors was found in 100% meningothelial, 95% transitional, 46% fibrous and 78% atypical variant of meningiomas. Intensity of immunoreaction was stronger in grade I than in grade II tumors. Immunoexpression of estrogen receptors was found in 48% of the investigated meningiomas. No correlation was stated between WHO grade I and grade II tumors, and between meningothelial, transitional and fibrous variants of the neoplasms.
- MeSH
- financování organizované MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- meningeom metabolismus patologie MeSH
- nádory mozku metabolismus patologie MeSH
- receptory pro estrogeny biosyntéza MeSH
- receptory progesteronu biosyntéza MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
