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Oestrogen receptor-alpha regulates non-canonical Hedgehog-signalling in the mammary gland.

Mesenchymal dysplasia (mes) mice harbour a truncation in the C-terminal region of the Hh-ligand receptor, Patched-1 (mPtch1). While the mes variant of mPtch1 binds to Hh-ligands with an affinity similar to that of wild type mPtch1 and appears to normally regulate canonical Hh-signalling via smoothened, the mes mutation causes, among other non-lethal defects, a block to mammary ductal elongation at puberty. We demonstrated previously Hh-signalling induces the activation of Erk1/2 and c-src independently of its control of smo activity. Furthermore, mammary epithelial cell-directed expression of

Estrogen and the Ca2+-mobilizing agonist ATP evoke acute NO synthesis via distinct pathways in an individual human vascular endothelium-derived cell.

In this study, we have systematically evaluated the signaling mechanisms underlying stimulated nitric oxide (NO) synthesis by estrogen (E2) and other vasoactive agents at the level of a single endothelium-derived cell. To do so, we have characterized and contrasted rapid E2-evoked NO synthesis with that of ATP using single-cell microfluorimetry and patch-clamp recordings to monitor stimulated changes in cellular NO synthesis (via 4-amino-5-methylamino-2',7'-difluorofluorescein), Ca2+ transients (via Fluo-3), and membrane hyperpolarization in cultured human EA.hy926 cells. E2-evoked NO synthesi

Effect of prolonged hydroxytamoxifen treatment of MCF-7 cells on mitogen activated kinase cascade.

Resistance to the antiestrogen tamoxifen is the main stumbling block for the success of breast cancer therapy. We focused our study on cellular alterations induced by a prolonged treatment with the active tamoxifen metabolite hydroxytamoxifen (OHT). We show that a prolonged OHT treatment (for up to 7 days) led to a progressive increase in the level of phosphorylated p44/42 mitogen activated kinase (MAP kinase) induced by 10(-7) M TPA stimulation, without any significant change in the protein level. This effect was also observed in MCF-7 cells grown first in medium containing dextran-coated cha

Isopropanolic extract of black cohosh stimulates osteoprotegerin production by human osteoblasts.

UNLABELLED: An isopropanolic extract (iCR) from the rhizomes of Cimicifuga racemosa (black cohosh) is used an alternative in the treatment of menopausal symptoms, and animal studies suggest positive skeletal effects. iCR stimulated osteoblastic OPG protein secretion by 3- to 5-fold as early as 12 h without affecting RANKL expression. The iCR effect, abrogated by the pure estrogen receptor antagonist ICI 182,780, also enhanced ALP activity (4-fold) and osteocalcin expression (3-fold), possibly contributing to the skeletal effects of black cohosh. INTRODUCTION: Despite its positive effects on t

Cyr61 promotes breast tumorigenesis and cancer progression.

Cyr61, a member of the CCN family of genes, is an angiogenic factor. We have shown that it is overexpressed in invasive and metastatic human breast cancer cells and tissues. Here, we investigated whether Cyr61 is necessary and/or sufficient to bypass the 'normal' estrogen (E2) requirements for breast cancer cell growth. Our results demonstrate that Cyr61 is sufficient to induce MCF-7 cells to grow in the absence of E2. Cyr61-transfected MCF-7 cells (MCF-7/Cyr61) became E2-independent but still E2-responsive. On the other hand, MCF-7 cells transfected with the vector DNA (MCF-7/V) remain E2-dep

Update Breast Cancer 2019 Part 5 - Diagnostic and Therapeutic Challenges of New, Personalised Therapies in Patients with Advanced Breast Cancer.

Significant advancements have been made in recent years in advanced breast cancer and nearly all of them have been in the field of targeted therapy. Pertuzumab and trastuzumab-emtansine (T-DM1) have been able to be introduced in HER2-positive breast cancer. Now other anti-HER2 therapies are being developed (e.g. margetuximab, DS-8201a, pyrotinib) which can overcome other resistance mechanisms in the HER2 signalling pathway. In the field of hormone-receptor-positive breast cancer, an mTOR inhibitor and CDK4/6 inhibitors were introduced in the past. Now the introduction of the first PI3K inhibit

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… Fulvestrant/OFS | Letrozole | Fulvestrant | Letrozole/OFS | Fulvestrant Fulvestrant/OFS | NSAI Median dose intensity | Palbociclib: 94% | Palbociclib: 93% Letrozole: 100% Placebo: 100% | Palbociclib: 86% 55 Placebo: 98% 55 | Ribociclib: 87.5% 57 Letrozole: 100% 57 Placebo: 100% 57 | Ribociclib: 92.1% … In the randomised SOLAR-1 study, patients who had already received antihormone therapy were randomised for therapy with fulvestrant vs. fulvestrant + alpelisib (PI3K inhibitor). …

Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy.

The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of the rapamycin (mTOR) axis is a key signal transduction system that links oncogenes and multiple receptor classes which are involved in many essential cellular functions. Aberrant PI3K signalling is one of the most commonly mutated pathways in cancer. Consequently, more than 40 compounds targeting key components of this signalling network have been tested in clinical trials among various types of cancer. As the oncogenic activation of the PI3K/AKT/mTOR pathway often occurs alongside mutations in other signalling

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… In the same setting, the BELLE 3 trial demonstrated that buparlisib plus fulvestrant was associated with better progression-free survival (PFS) compared to fulvestrant alone (median 3.9 months versus 1.8 months; HR 0.67 CI 0.53–0.84; p < 0.001), especially in patients with a real-time polymerase chain … Of note, this study found out that these patients with different PI3KCAm also have longer PFS when administered with alpelisib plus fulvestrant compared to fulvestrant alone [ 71 ]. …

E2112: randomized phase iii trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer.

Endocrine therapies are effective in the treatment of hormone receptor (HR)-positive breast cancer, however, de novo or acquired treatment resistance is a significant clinical problem. A potential mechanism of resistance involves changes in gene expression secondary to epigenetic modifications, which might be reversed with the use of histone deacetylase (HDAC) inhibitors such as entinostat. The ENCORE 301 phase II randomized, placebo-controlled study demonstrated a significant improvement in progression-free survival (PFS) and overall survival (OS), with the addition of entinostat to exemestan

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… Stratification factors include setting in which patient developed resistance to prior non-steroidal AI (adjuvant/metastatic), geographic region, presence of visceral disease and prior fulvestrant use. … Cristofanilli M Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial …

Gene expression profiling of testosterone and estradiol-17 beta-induced prostatic dysplasia in Noble rats and response to the antiestrogen ICI 182,780.

We previously demonstrated that 1) treatment of Noble rats for 16 wk with testosterone (T) and estradiol-17 beta (E2) led to 100% incidence of dorsolateral prostate (DLP) dysplasia and hyperprolactinemia and 2) blockade of PRL release with bromocriptine cotreatment significantly lowered the incidence of DLP dysplasia. In the current study, we sought to determine whether E2 exerts direct effects, independent of PRL, in this model system. The pure antiestrogen ICI 182,780 (ICI), reported to have no effect on PRL release in female rats, was administered biweekly to T + E2-treated rats at 3 mg/kg

Palbociclib: A New Option for Front-Line Treatment of Metastatic, Hormone Receptor-Positive, HER2-Negative Breast Cancer.

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… The PALOMA-3 trial was also a randomized (2:1), multicenter, double-blind phase III study evaluating palbociclib in combination with an alternative antiestrogen, fulvestrant (Faslodex), vs. fulvestrant plus placebo in patients with HR+, HER2– MBC. … Patients who would be a candidate for palbociclib are typically also candidates for fulvestrant; when fulvestrant is combined with an AI, there have been similar survival data and a more favorable toxicity profile, with no risk of myelosuppression ( Mehta et al., 2012 ). …

Comparative analysis of Denosumab and Zoledronic acid in advanced breast cancer patients receiving CDK4/6 inhibitors.

A comparative analysis of Denosumab (DMAB) and Zoledronic Acid (ZA) was conducted in a real-world cohort of 864 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer with bone metastases, who were undergoing CDK4/6 inhibitors plus endocrine therapy. We evaluated the time to first skeletal-related events (SREs), progression-free survival (PFS), and overall survival (OS). To adjust for confounding variables, we utilized propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) methodologies. In the unadjusted

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… Monarch 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy J Clin Oncol 35 2017 2875 2884 28580882 10.1200/JCO.2017.73.7585 12 Sledge G.W. … Overall survival with Palbociclib and fulvestrant in advanced breast cancer N Engl J Med 379 2018 1926 1936 30345905 10.1056/NEJMoa1810527 17 Rugo H.S. …

Pharmacologic management of bone-related complications and bone metastases in postmenopausal women with hormone receptor-positive breast cancer.

There is a high risk for bone loss and skeletal-related events, including bone metastases, in postmenopausal women with hormone receptor-positive breast cancer. Both the disease itself and its therapeutic treatments can negatively impact bone, resulting in decreases in bone mineral density and increases in bone loss. These negative effects on the bone can significantly impact morbidity and mortality. Effective management and minimization of bone-related complications in postmenopausal women with hormone receptor-positive breast cancer remain essential. This review discusses the current underst

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… treated with fulvestrant as first-line therapy in locally advanced breast cancer, fulvestrant did not increase the bone turnover markers BAP, PINP, and CTX. 58 Given the small number of patients in this trial, it is unclear what impact the seemingly bone-neutral effects of fulvestrant might have in … Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594–4600. doi: 10.1200/JCO.2010.28.8415. 22. …

Palbociclib as an Antitumor Drug: A License to Kill.

Neoplastic cells are characterized by uncontrolled cell divisions caused by cell cycle dysregulation. Key regulatory proteins governing the transition from the G1 to the S phase are the CDK4 and CDK6 kinases, which are controlled by D-type cyclins. The CDK4/6 kinases enable the use of these proteins as targets for anticancer therapy because they prevent the growth and the development of malignant cells by inhibiting their activity. This paper surveys the clinical trial results concerning palbociclib, the first in-class FDA-approved anticancer drug for hormone-dependent breast cancer. It discus

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… The impact of palbociclib addition to the fulvestrant or fulvestrant and avelumab on patients whose disease progressed after previous CDK4/6 inhibitor plus endocrine therapy treatment was evaluated in the PACE clinical trial ( Table 2 ). … The results showed that the implementation of the palbociclib–fulvestrant combination therapy did not improve the progression-free survival (4.8 months for fulvestrant alone vs. 4.6 months for palbociclib–fulvestrant); however, additional immunotherapy with avelumab improved the progression-free survival …

Multi-antigen-targeted T-cell therapy to treat patients with relapsed/refractory breast cancer.

PurposeAdoptively transferred, ex vivo expanded multi-antigen-targeted T cells (multiTAA-T) represent a new, potentially effective, and nontoxic therapeutic approach for patients with breast cancer (BC). In this first-in-human trial, we investigated the safety and clinical effects of administering multiTAA T cells targeting the tumor-expressed antigens, Survivin, NY-ESO-1, MAGE-A4, SSX2, and PRAME, to patients with relapsed/refractory/metastatic BC.Materials and methodsMultiTAA T-cell products were generated from the peripheral blood of heavily pre-treated patients with metastatic or locally r

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… , ER+ PR+ HER2− | Breast, LNs, bones, liver | - Letrozole - Fulvestrant + palbociclib - Capecitabine | 2 | PD (2 months) | Deceased (20 months) 9 | 62 | IDC, ER+, PR+ HER2− | Lungs, liver, pleural effusion and bones | - 5FU + doxorubicin + cyclophosphamide - Tamoxifen - Anastrazole + OS - Fulvestrant … - Letrozole - Everolimus + exemestane - Letrozole + palbociclib - Capecitabine - High-dose estradiol - Paclitaxel | 5 | SD (5 months) | Deceased (27 months) 10 | 63 | ILC, ER+ PR+ HER2− | Bones | - Neoadjuvant tamoxifen - Adjuvant anastrazole - Everolimus + Exemestane - Fulvestrant - Fulvestrant + palbocicilib …

A national portfolio of bone oncology trials-The Canadian experience in 2012.

BackgroundThe impact of both cancer and its treatment on bone is an essential component of oncological practice. Bone oncology not only affects patients with both early stage and metastatic disease but also covers the entire spectrum of tumour types. We therefore decided to review and summarise bone oncology-related trials that are currently being conducted in Canada.MethodWe assessed ongoing and recently completed trials in Canada. We used available North American and Canadian cancer trial websites and also contacted known investigators in this field for their input.ResultsTwenty seven clinic

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… . | 2 | 50 | Prostate A phase ii, multi-centre, randomized, double-blind trial to evaluate the therapeutic benefit of Fulvestrant in combination with ZACTIMA or Fulvestrant Plus Placebo in postmenopausal women with bone only or bone predominant, hormone receptor positive metastatic breast cancer [16] … | Fulvestrant+Zactima versus Fulvestrant+Placebo | Significant change in NTx level defined as a ≥30% reduction in urinary NTx level from baseline | Multi-centre | 126 | Breast A multicentre study assessing 12-weekly intravenous bisphosphonate therapy in women with low risk bone metastases from breast …

Impact of the National Health Insurance Coverage Policy on the Utilisation and Accessibility of Innovative Anti-cancer Medicines in China: An Interrupted Time-Series Study.

Objective: The study aimed to evaluate the impact of the National Health Insurance Coverage (NHIC) policy on the utilisation and accessibility of innovative anti-cancer medicines in Nanjing, China. Methods: We used the adjusted World Health Organisation and Health Action International methodology to calculate the price and availability of 15 innovative anti-cancer medicines included in the National Health Insurance drug list in 20 tertiary hospitals and six secondary hospitals in Nanjing before and after NHIC policy implementation. Interrupted time-series regression was used to analyse the cha

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… With the PAP, only fulvestrant could be affordable. … Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. …

Long-Term Management of Breast Cancer Bone Metastases: Two Case Reports.

Patients with advanced HR+/HER2- breast cancer often experience prolonged disease courses, with bone being a dominant site of metastasis. Bone-targeted agents (BTAs) are recommended to reduce the risk of skeletal-related events (SREs), yet most clinical trials report follow-up durations of less than 2 years. Here, we present two cases of patients with breast cancer and bone metastases who received continuous BTA therapy for 8 and 10 years, respectively, in the context of ongoing antitumor treatment. Neither patient developed SREs during follow-up. The two cases demonstrated good tolerabilit du

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… Second-line treatment (Apr. 2021–Sep. 2022) | Fulvestrant + palbociclib | Denosumab 120 mg Q4W | Stable disease Progression: In September 2022, PET-CT and biopsy confirmed liver metastasis. … Fourth-line treatment (Feb 2022–Feb 2024) | Abemaciclib + fulvestrant | Denosumab 120 mg Q4W | Partial response In March 2024, a progression of liver metastases was observed. …

Role of Cyclin-Dependent Kinase Inhibitors in Endometrial Cancer.

Endometrial Cancer (EC) is an important cause of death in women worldwide. Despite early diagnosis and optimal treatment of localized disease, relapsed patients have few therapeutic options because after first line therapy, currently no standard of care exists. On the basis of endocrine positivity of most endometrioid ECs, Endocrine Therapy (ET) is a reasonable and widely accepted option. Better knowledge of molecular mechanisms involved in cancer highlighted the deregulated activity of Cyclin-Dependent Kinases (CDKs) in the cell cycle as a hallmark of carcinogenesis supporting the development

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… It suggested that mutation of RB is a driver mutation in the palbociclib plus fulvestrant arm while mutations of PI3KCA (gene encoding for PI3K) and ESR1 (gene encoding for ER1) are driver mutations in both arms (fulvestrant alone and fulvestrant plus palbociclib), playing a main role in acquired endocrine … The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial. Cancer Discov. 2018;8:1390–1403. doi: 10.1158/2159-8290.CD-18-0264. 64. Corona S.P., Generali D. …

Monitoring concentration and lipid signature of plasma extracellular vesicles from HR+ metastatic breast cancer patients under CDK4/6 inhibitors treatment.

Extracellular vesicles (EVs) are cell-derived small membrane structures that transport various molecules. They have emerged as potential circulating biomarkers for monitoring responses to cancer therapies. This study aimed to comprehensively characterize plasma-carried EVs in hormone receptor-positive (HR+) metastatic breast cancer (MBC) patients treated with first-line CDK4/6 inhibitors (iCDK4/6) combined with endocrine therapy. MBC patients were classified into three groups based on their response to therapy: resistant, intermediate or sensitive. In a prospective cohort, we monitored the con

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… Switching from aromatase inhibitor and palbociclib treatment to fulvestrant and palbociclib upon detection of rising bESR1 mutations led to significantly improved progression‐free survival (Bidard et al., 2022 ). … | x | x | x | NST | III | 100 | 5 | + #048 | 55 | 6 | NO | Abemaciclib a + Fulvestrant | x | | x | ILC | II | 100 | 20 | neg #056 | 52 | 6 | NO | Ribociclib a + Fulvestrant | x | x | x | NST | II | 100 | 100 | neg #072 | 56 | 2 | NO | Ribociclib a + Fulvestrant | x | x | x | NST | III | 95 | 75 | neg …

Drug repurposing for breast cancer therapy: Old weapon for new battle.

Despite tremendous resources being invested in prevention and treatment, breast cancer remains a leading cause of cancer deaths in women globally. The available treatment modalities are very costly and produces severe side effects. Drug repurposing that relate to new uses for old drugs has emerged as a novel approach for drug development. Repositioning of old, clinically approved, off patent non-cancer drugs with known targets, into newer indication is like using old weapons for new battle. The advances in genomics, proteomics and information computational biology has facilitated the process o

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… Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial Lancet Oncol. … Overall survival with fulvestrant plus anastrozole in metastatic breast cancer N. Engl. J. Med. 380 13 2019 1226 1234 30917258 10.1056/NEJMoa1811714 PMC6885383 122 Nathan M.R. Schmid P. A review of fulvestrant in breast cancer Oncol. …