- Association of Wnt Inhibitors, Bone Mineral Density and Lifestyle Parameters in Women with Breast Cancer Treated with Anastrozole Therapy. [Journal Article]
- JCJ Clin Med 2018 Sep 17; 7(9)
- CONCLUSIONS: AI treatment was associated with increased levels of sclerostin and decreased levels of DKK1.
- Fulvestrant plus goserelin versus anastrozole plus goserelin versus goserelin alone for hormone receptor-positive, HER2-negative tamoxifen-pretreated premenopausal women with recurrent or metastatic breast cancer (KCSG BR10-04): a multicentre, open-label, three-arm, randomised phase II trial (FLAG study). [Journal Article]
- EJEur J Cancer 2018 Sep 14; 103:127-136
- CONCLUSIONS: F + G provides a promising new option for the treatment of premenopausal women with HR+, HER2-, tamoxifen-pretreated MBC.
- Clinical utility of fulvestrant in the treatment of breast cancer: a report on the emerging clinical evidence. [Review]
- CMCancer Manag Res 2018; 10:3083-3099
- Fulvestrant is the first selective estrogen receptor (ER) downregulator available in clinical practice. It is a pure antiestrogen with no agonistic effects, leading to degradation of ER alpha, with a...
Fulvestrant is the first selective estrogen receptor (ER) downregulator available in clinical practice. It is a pure antiestrogen with no agonistic effects, leading to degradation of ER alpha, with activity in tamoxifen-resistant breast cancer (BC) models. Pharmacokinetic and pharmacodynamic studies and several postmarketing clinical trials led to the definition of the optimal dose at 500 mg intramuscularly on days 1, 15, and 29 and then every 28 days. Targeting ER alpha, fulvestrant is a cornerstone of treatment in luminal BCs, whose growth is largely driven by the ER pathway. In endocrine therapy-naïve patients with hormone receptor-positive, HER2- advanced BC (ABC), fulvestrant yielded significantly longer progression-free survival compared to anastrozole in the Phase III FALCON study. Due to its mechanism of action and pharmacokinetic properties, fulvestrant is an ideal backbone for combination therapies. Preclinical studies have shown synergism with drugs acting on signaling pathways involved in the development of endocrine resistance, among which the cyclin D/cyclin-dependent kinase 4-6/retinoblastoma pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway, contributing to overcoming or delaying endocrine resistance. In the Phase III PALOMA-3 trial, a combination of the cyclin-dependent kinase 4/6 inhibitor palbociclib with fulvestrant significantly improved progression-free survival over fulvestrant alone in women with hormone receptor positive, HER2- ABC progressing during prior endocrine therapy. This led to approval of the combination in this clinical setting. Similar results were obtained with abemaciclib and ribociclib. Combination with pan-PI3K inhibitors, though showing some efficacy, was hampered by the toxicity of these agents, and studies in combinations with more selective inhibitors of the α-catalytic subunit of PI3K are ongoing. Fulvestrant has shown partial activity also in patients with tumors harboring mutations of the ESR1 gene. It is thus a key drug in the treatment of ABC, whose role in combination with new targeted agents is still evolving.
- Exploratory Study of Associations Between DNA Repair and Oxidative Stress Gene Polymorphisms and Cognitive Problems Reported by Postmenopausal Women With and Without Breast Cancer. [Journal Article]
- BRBiol Res Nurs 2018 Sep 13; :1099800418799964
- CONCLUSIONS: Chemotherapy plus anastrozole, depressive symptoms, and presence of neuropathic symptoms may predict more frequent cognitive problems during systemic therapy that later resolve. Mood dysregulation before therapy may predict persistent cognitive problems during therapy. ERCC5 genotype may influence frequency of cognitive problems after controlling for these risk factors.
- Novel 18-gene signature for predicting relapse in ER-positive, HER2-negative breast cancer. [Journal Article]
- BCBreast Cancer Res 2018 Sep 04; 20(1):103
- CONCLUSIONS: The derived 10-year signature predicts risk of metastasis in patients with ER+/HER2- breast cancer similar to commercial signatures. The hypothesis that early and late prognostic signatures are significantly more informative than a single signature was rejected.
- Polyphenolic natural products and natural product-inspired steroidal mimics as aromatase inhibitors. [Review]
- MRMed Res Rev 2018 Sep 01
- The discovery of biologically active polyphenolic natural products, including chalcones, stilbenes, flavanones, and isoflavones as steroidal mimics has proven to be a subject of considerable importan...
The discovery of biologically active polyphenolic natural products, including chalcones, stilbenes, flavanones, and isoflavones as steroidal mimics has proven to be a subject of considerable importance in medicine. Some of these natural compounds have been shown to modulate key human metabolic processes via steroidal hormone receptors, or to inhibit crucial enzymes involved in the biosynthesis of steroidal hormones themselves. Isoflavone polyphenolics such as genistein are well known for this "phytoestrogenic" biological activity. This review focuses on the ability of select polyphenolics and their synthetic derivatives to function as steroidal mimics in the inhibition of the enzyme aromatase, thereby lowering production of endogenous estrogen growth hormones. The discovery of potent, natural product-based aromatase inhibitors (AIs) as hit compounds has led to the introduction of steroidal-based irreversible inhibitors, such as exemestane and reversible AIs such as anastrozole and letrozole, now standard therapy in the treatment of estrogen receptor-positive breast cancer and other hormone related indications. Pursuit of this strategy over the last few decades has been largely successful although complications and challenges remain. This review highlights the aromatase activity of natural stilbenes, chalcones, and flavanones and synthetically inspired versions thereof and draws attention to new and under-investigated areas within each class worthy of pursuit.
- Synthetic isoflavones and doping: a novel class of aromatase inhibitors? [Journal Article]
- DTDrug Test Anal 2018 Aug 17
- Anectodical information suggests that flavonoids may be widely used among athletes for their multiple biochemical and pharmacological effects. We have evaluated in vitro the effects of two synthetic ...
Anectodical information suggests that flavonoids may be widely used among athletes for their multiple biochemical and pharmacological effects. We have evaluated in vitro the effects of two synthetic isoflavones, methoxyisoflavone and ipriflavone, on the catalytic activity of human aromatase (CYP19), the enzyme catalyzing the conversion of androgens (i.e. testosterone or androstenedione) to estrogens (i.e. estradiol and estrone). The potential inhibitory effect was evaluated by measuring the rate of aromatization of testosterone, monitored by GC-MS, both in the presence and in the absence of methoxyisoflavone or ipriflavone, comparing their effects with those of synthetic aromatase inhibitors (formestane, anastrozole and aminoglutethimide) presently included in the list of prohibited substances and methods, and of natural flavonoids (chrysin, quercetin and daidzein), that are known inhibitors of CYP19. The preliminary results of our in vitro study show that methoxyisoflavone and ipriflavone act as competitive inhibitors of aromatase, the degree of inhibition measured in vitro being of the same order of magnitude of that of the aromatase inhibitors commonly used in anti-estrogenic therapies. Our preliminary in vitro results indicate that, in principle, a sufficiently large intake of isoflavones could alter the kinetics of the dynamic equilibria between androgens and estrogens, suggesting their monitoring in doping control routine analysis.
- First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2-Positive and Hormone Receptor-Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial. [Journal Article]
- JCJ Clin Oncol 2018 Aug 14; :JCO2017767863
- Purpose To assess pertuzumab plus trastuzumab and an aromatase inhibitor (AI) in patients with human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive metastatic/locall...
Purpose To assess pertuzumab plus trastuzumab and an aromatase inhibitor (AI) in patients with human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive metastatic/locally advanced breast cancer (MBC/LABC). Patients and Methods The PERTAIN trial (NCT01491737) is an ongoing randomized, open-label, multicenter-80 sites and eight countries-phase II trial. Patients have HER2-positive, hormone receptor-positive MBC/LABC and no prior systemic therapy with the exception of endocrine. Random assignment was 1:1 to intravenous pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks) plus trastuzumab (8 mg/kg followed by 6 mg/kg every 3 weeks), and oral anastrozole (1 mg every day) or letrozole (2.5 mg every day), or trastuzumab and an AI. Induction intravenous docetaxel every 3 weeks or paclitaxel every week could be administered for 18 to 24 weeks at the investigator's discretion (decided before but given after random assignment). Primary end point was progression-free survival (PFS). Patients were stratified by whether they received induction chemotherapy and their time since adjuvant hormone therapy. Results One hundred twenty-nine patients were randomly assigned per arm (February 2012 to October 2014; intent-to-treat populations); 75 in one arm and 71 in the other were chosen to receive induction chemotherapy. Stratified median PFS was 18.89 months (95% CI, 14.09 to 27.66 months) in the pertuzumab plus trastuzumab arm and 15.80 months (95% CI, 11.04 to 18.56 months) in the trastuzumab arm (stratified hazard ratio, 0.65; 95% CI, 0.48 to 0.89; P = .0070). Serious adverse events (AEs) were reported for 42 (33.1%) of 127 and 24 (19.4%) of 124 patients in the safety populations of the pertuzumab plus trastuzumab and trastuzumab arms, respectively. Rates of grade ≥ 3 AEs were 64 (50.4%) of 127 and 48 (38.7%) of 124, respectively. There were no deaths as a result of AEs. Conclusion PERTAIN met its primary PFS end point. Pertuzumab plus trastuzumab and an AI is effective for the treatment of HER2-positive MBC/LABC. The safety profile was consistent with previous trials of pertuzumab plus trastuzumab.
- FPSE-HPLC-DAD method for the quantification of anticancer drugs in human whole blood, plasma, and urine. [Journal Article]
- JCJ Chromatogr B Analyt Technol Biomed Life Sci 2018 Jul 31; 1095:204-213
- The present work describes a fast, sensitive and selective procedure for the analyses of aromatase inhibitors including anastrozole, letrozole and exemestane used in the treatment of metastatic breas...
The present work describes a fast, sensitive and selective procedure for the analyses of aromatase inhibitors including anastrozole, letrozole and exemestane used in the treatment of metastatic breast cancer by high performance liquid chromatography (HPLC) in human whole blood, plasma, and urine samples succeeding an extraction by innovative fabric phase sorptive extraction (FPSE). These drugs were successfully determined using a Luna C18 column at 25 °C using acetonitrile and phosphate buffer. The analytical method was validated, using weighted-matrix matched standard calibration curves. The intra- and inter-day accuracy values (precision and trueness) fulfill the criteria of International Guidelines on Bioanalytical Methods Validation. The analytical performances were further tested on real human biological samples. To the best of our knowledge, this is the first FPSE procedure applied to human whole blood, plasma, and urine samples for the concurrent analysis of aromatase inhibitors possessing a wide range of polarity index values and could be easily adopted as a rapid and green analytical protocol for clinical and pharmaceutical applications. The proposed HPLC method is very innovative since in the literature there are only methods dealing with a single antitumoral drug, and no process has been described so far for these three antitumoral drugs together directly from the whole blood.
New Search Next
- Everolimus. [Journal Article]
- RRRecent Results Cancer Res 2018; 211:101-123
- Everolimus (RAD001) is an oral protein kinase inhibitor of the mTOR (mammalian target of rapamycin) serine/threonine kinase signal transduction pathway. The mTOR pathway regulates cell growth, prolif...
Everolimus (RAD001) is an oral protein kinase inhibitor of the mTOR (mammalian target of rapamycin) serine/threonine kinase signal transduction pathway. The mTOR pathway regulates cell growth, proliferation and survival, and is frequently deregulated in cancer.The EMA has approved Everolimus as Afinitor® for the treatment of hormone receptor-positive, HER2/neu-negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a nonsteroidal aromatase inhibitor, for the treatment of unresectable or metastatic, well- or moderately differentiated neuroendocrine tumors of pancreatic origin in adults with progressive disease, and for the treatment of unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) nonfunctional neuroendocrine tumors of gastrointestinal or lung origin in adults with progressive disease, and for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF-targeted therapy And as Votubia® for the treatment of adult patients with renal angiomyolipoma associated with tuberous sclerosis complex (TSC), who are at risk of complications (based on factors such as tumor size or presence of aneurysm, or presence of multiple or bilateral tumors) but who do not require immediate surgery, and for the treatment of patients with subependymal giant cell astrocytoma (SEGA) associated with TSC who require therapeutic intervention but are not amenable to surgery, and as an add-on treatment in patients from 2 years of age with seizures related to TSC that have not responded to other treatments (https://www.novartis.com/news/media-releases/novartis-drug-votubiar-receives-eu-approval-treat-refractory-partial-onset). The FDA has approved Everolimus as Afinitor® for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after the failure of treatment with letrozole or anastrozole, for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease, for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or sorafenib, for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. for the treatment of adult and pediatric patients, 3 years of age or older, with SEGA associated with TSC who require therapeutic intervention but are not candidates for curative surgical resection. Everolimus shows promising clinical activity in additional indications. Multiple Phase II and Phase III trials of everolimus alone or in combination and will help to further elucidate the role of mTOR in oncology. For a review on everolimus as immunosuppressant, please consult other sources.