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Heterogeneous tissue-specific macrophages orchestrate metastatic organotropism of breast cancer: implications for promising therapeutics.

Compelling evidences have manifested that breast cancer cells prefer to metastasize to certain distant organs, including brain, lung, bone and liver. According to the canonical "seed and soil" theory, this prominent biological behavior, termed as metastatic organotropism, involves intricate interactions between breast cancer cells (the "seeds") and specific residents in the tumor microenvironment (the "soil"), initiating from pre-metastatic niche formation to metastatic outgrowth. Recently, multifaceted heterogeneity of tissue-specific macrophages (TSMs) and their roles played in organotropic

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… The phase 3 BELLE-2 trial ( NCT01610284 ) examining buparlisib and fulvestrant in postmenopausal endocrine-resistant HR + /HER2– MBC attained a significantly improved PFS in the total, known PI3K status and PI3K-activated population, suggesting the effectiveness of combining PI3K inhibition and endocrine … The MEK1/2 inhibitor selumetinib in combination with buparlisib or pazopanib (a PDGFR inhibitor) improved survival and suppressed relevant signaling in mice bearing some sensitive metastatic TNBC cell lines with intracranial metastases [ 149 ], but the addition of selumetinib to fulvestrant in aromatase …

Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer.

The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/ER(lo) cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133(hi)/ER(lo)/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)

Recent advances in development of CDK7 inhibitors and their clinical trials: a narrative review.

Background and objectiveCDK7, a member of the CDK-activating kinase (CAK) family, plays a key role in cell cycle, transcriptional regulation and in regulating the proliferation and apoptosis of tumor cells. Some evidence suggests that CDK7 is a promising target for cancer treatments, so it is of great significance to develop an efficient and highly selective CDK7 inhibitor. CDK7 inhibitors have not yet been marketed. This review focuses on some selective CDK7 inhibitors currently in clinical research, and introduces their targets, indications, and the latest clinical trial progress in detail.M

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… Besides, for combination expansion cohort experiments, drug Fulvestrant is administered with XL-102 in subjects with HR + BC (Cohort H). Drug Abiraterone/Prednisone is administered with XL-102 in subjects with mCRPC (Cohort I). … In addition to monotherapy, SY-5609 is being developed in combination with: (I) Fulvestrant for CDK4/6 inhibitor-refractory HR + /HER2 – breast cancer. …

The EPICURE study: a pilot prospective cohort study of heterogeneous and massive data integration in metastatic breast cancer patients.

BackgroundBreast cancer is the most common cancer in women and the first cancer concerning mortality. Metastatic breast cancer remains a disease with a poor prognosis and about 30% of women diagnosed with an early stage will have a secondary progression. Metastatic breast cancer is an incurable disease despite significant therapeutic advances in both supportive cares and targeted specific therapies. In the management of a metastatic patient, each clinician follows a highly complex and strictly personal decision making process. It is based on a number of objective and subjective parameters whic

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… Cristofanilli M Turner NC Bondarenko I Ro J Im S-A Masuda N 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 … Baselga J Im S-A Iwata H Cortés J De Laurentiis M Jiang Z Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial Lancet Oncol 2017 18 7 904 …

Recurrent severe hypocalcemia following chemotherapy regimen changes in advanced breast cancer: two case reports.

BACKGROUND: As an oncologic emergency related to abnormalities in calcium metabolism, hypercalcemia associated with paraneoplastic syndrome and bone metastases is well known. Meanwhile, the incidence of hypocalcemia is low, except in cases associated with bone-modifying agents used for bone metastases. Hypocalcemia induced by bone-modifying agents typically occurs early after the initial administration, and its incidence can be significantly reduced by preventive administration of calcium and vitamin D3 supplements. CASE REPORT: We report two cases of recurrent severe hypocalcemia occurring d

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… In year Y + 2, she developed multiple bone metastases and received fulvestrant, denosumab, and precipitated calcium carbonate/cholecalciferol/magnesium carbonate. In year Y + 3, the regimen was switched to letrozole and lapatinib therapy owing to bone metastases progression. … She had a positive response to letrozole monotherapy for 4 months followed by fulvestrant for 3 months. The regimen was switched to trastuzumab emtansine (T-DM1) owing to progression of the bone metastases. …

Clinical Actionability of Molecular Targets in Multi-Ethnic Breast Cancer Patients: A Retrospective Single-Institutional Study.

BACKGROUND: Precision oncology is making remarkable advancements in optimizing patient care by personalizing treatments. To date, the US Food and Drug Administration (FDA) has approved poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib (Lynparza, AstraZeneca and Merck) and talazoparib (Talzenna, Pfizer Oncology Together™) for germline or somatic BRCA1/2-mutated metastatic breast cancer (BC) patients, and PI3K inhibitor alpelisib (Piqray, Novartis) plus fulvestrant for patients with hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+HER2-) PIK3CA-mutated advanc…

Wisely frugal: ensuring sustainable funding for novel cancer therapeutics through a budget impact analysis in resource-limited settings.

IntroductionCancer care in Sri Lanka is predominantly provided through its state health system which is free at the point of delivery. We performed a budget impact analysis of novel cancer drugs with a view to enabling better prioritising of their procurement.MethodsMedian survival gain was obtained for each indication of a novel cancer drug by a review of the literature. The direct cost of drug procurement was obtained from the Ministry of Health of Sri Lanka and the cost per life year gained was computed for each indication. Two thresholds - per capita gross domestic product (GDP) per life y

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… | 1,889,789 Abiraterone 1,000 mg | Metastatic castration resistant prostate cancer (Post docetaxel) | 20% | 4 | 3.9 months | 1,158 | 3,562 | 0.93 | 100 | 115,771 Cabazitaxel | Metastatic castration resistant prostate cancer (Post docetaxel) | 50% | 3 | 2.6 months | 774 | 3,573 | 0.94 | 100 | 77,423 Fulvestrant … Fulvestrant in the first and second line treatment of endocrine sensitive metastatic breast cancer. Sunitinib in the first line treatment of metastatic renal cell carcinoma treatment of gastrointestinal stromal tumour (GIST). …

Prioritising systemic cancer therapies applying ESMO's tools and other resources to assist in improving cancer care globally: the Kazakh experience.

BackgroundIn Kazakhstan, cancer is the second leading cause of death with a major public health and economic burden. In the last decade, cancer care and cancer medicine costs have significantly increased. To improve the efficiency and efficacy of cancer care expenditure and planning, the Kazakhstan Ministry of Health requested assistance from the World Health Organization (WHO) and the European Society for Medical Oncology (ESMO) to review its systemic cancer treatment protocols and essential medicines list and identify high-impact, effective regimens.Materials and methodsESMO developed a four

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… neoadjuvant HER2-positive tumours | A | 9 Trastuzumab and docetaxel + pertuzumab | Neoadjuvant HER2-overexpressed invasive ductal breast | C b | 10 , 11 Trastuzumab + docetaxel + pertuzumab | First line metastatic | 4 | 12 , 13 , 14 , 15 Lapatinib + trastuzumab | Third line metastatic | 4 | 16 , 17 Fulvestrant … 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 17 …

Molecular therapies for systemic lupus erythematosus: clinical trials and future prospects.

The prognosis of patients with systemic lupus erythematosus has greatly improved since treatment regimens combining corticosteroids and immunosuppressive medications have been widely adopted in therapeutic strategies given to these patients. Immune suppression is evidently efficient but also leads to higher susceptibility to infectious and malignant diseases. Toxic effects and sometimes unexpectedly dramatic complications of current therapies have been progressively reported. Identifying novel molecular targets therefore remains an important issue in the treatment of lupus. The aim of this rev

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… In patients who received 250 mg fulvestrant intramuscularly for 12 months, the SLEDAI score improved significantly and conventional medications could be reduced [ 21 ]. … Fulvestrant (Faslodex), an estrogen selective receptor dowmodulator, in therapy of women with systemic lupus erythematosus. Clinical, serologic, bone density, and cell activation marker studies: a double-blind placebo-controlled trial. J Rheumatol. 2008;35:797. …

Cardiac Interventions in Patients With Active, Advanced Solid and Hematologic Malignancies: JACC: CardioOncology State-of-the-Art Review.

Invasive cardiac interventions are recommended to treat ST-segment elevation myocardial infarction, non-ST-segment elevation acute coronary syndromes, multivessel coronary disease, severe symptomatic aortic stenosis, and cardiomyopathy. These recommendations are based on randomized controlled trials that historically included few individuals with active, advanced malignancies. Advanced malignancies represent a significant competing risk for mortality, and there is limited evidence to inform the risks and benefits of invasive cardiac interventions in affected patients. We review the benefit con

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… Updated overall survival (OS) results from the phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2- advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB) J Clin Oncol 39 suppl 2021 1001 81 Sledge G.W. Jr. Toi M. Neven P. … The Effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial JAMA Oncol 6 1 2020 116 124 10.1001/jamaoncol.2019.4782 31563959 PMC6777264 82 Andre F. Ciruelos E. …

Therapeutic Perspectives on the Modulation of G-Protein Coupled Estrogen Receptor, GPER, Function.

Estrogens exert their physiological and pathophysiological effects via cellular receptors, named ERα, ERβ, and G-protein coupled estrogen receptor (GPER). Estrogen-regulated physiology is tightly controlled by factors that regulate estrogen bioavailability and receptor sensitivity, while disruption of these control mechanisms can result in loss of reproductive function, cancer, cardiovascular and neurodegenerative disease, obesity, insulin resistance, endometriosis, and systemic lupus erythematosus. Restoration of estrogen physiology by modulating estrogen bioavailability or receptor activity

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… Pan-PI3K inhibitors have fared poorly in clinical trials due to their toxicity, while the isoform-specific PI3K inhibitor, alpelisib, has been approved by the FDA as co-therapy with fulvestrant for patients with ER-positive, PI3Kalpha mutated advanced breast cancer ( 139 ). … FDA approval of alpelisib with fulveestrant followed the results of the SOLAR-1 trial that showed that patients receiving alpelisib with fulvestrant showed a median increase of 6 months of progression free survival. …

Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance.

One of the greatest obstacles to current cancer treatment efforts is the development of drug resistance by tumors. Despite recent advances in diagnostic practices and surgical interventions, many neoplasms demonstrate poor response to adjuvant or neoadjuvant radiation and chemotherapy. As a result, the prognosis for many patients afflicted with these aggressive cancers remains bleak. The insulin-like growth factor (IGF) signaling axis has been shown to play critical role in the development and progression of various tumors. Many basic science and translational studies have shown that IGF pathw

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… For example, IGFBP-3 appears to sensitize ER+ breast cancer cells to the anti-estrogen fulvestrant by inhibiting anti-apoptotic effects of GRP78, a binding partner of the caspase 7 complex. 27 Another prevalent form of breast cancer is HER2 receptor positive (HER2+), and drugs that work by targeting … A recent study using estrogen-resistant ER+ breast cancer cells demonstrated that dual treatment with fulvestrant and dasatinib, a nonspecific tyrosine kinase inhibitor, had superior outcomes when compared to combination fulvestrant and IGF-1R monoclonal antibody therapy. 33 This may be due to fact that …

"Don't Think Twice, It's All Right": Using Additional Data to Reduce Uncertainty Regarding Oncologic Drugs Provided Through Managed Access Agreements in England.

ObjectivesThe Cancer Drugs Fund (CDF) in England uses managed access agreements to facilitate additional data collection to address uncertainties identified in the appraisals of new drugs. This study reviews the uncertainties highlighted in the original appraisals where recommendations "to use within the CDF" were made and how additional data were used to address these uncertainties in the CDF review appraisals where final decisions on routine commissioning were made.MethodsThe first 24 drugs exiting the 2016 CDF were included in this review. The information about uncertainty and the use of ne

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… | – Base-case analysis (non-parametric use) | – | – | – | – | Treatment duration Support trial data Scenario/sensitivity analysis | – | – | – | – | – | TA674 | TA683 | TA684 | TA687 | TA691 Technology | Pembrolizumab | Pembrolizumab + pemetrexed and platinum chemotherapy | Nivolumab | Ribociclib + fulvestrant … SACT Systemic Anti-Cancer Therapy, TA technology appraisal Type of use | Drug | TA number Parametric use | Brentuximab vedotin | TA524 Pembrolizumab | TA766 Daratumumab | TA783 Ibrutinib | TA795 Venetoclax | TA796 Non-parametric use | Nivolumab | TA655 Avelumab | TA691 Nivolumab | TA713 Abemaciclib + fulvestrant …

Hypercalcemia of Malignancy and Medication-Related Osteonecrosis of the Jaw Following Denosumab Discontinuation in Metastatic Breast Cancer: A Case Report.

Hypercalcemia of malignancy (HCM) is a common and serious complication in patients with advanced cancer and is associated with significant morbidity and mortality. Standard long-term management of HCM relies on anti-resorptive therapies such as bisphosphonates and denosumab, both of which act by inhibiting osteoclast-mediated bone resorption but carry the risk of medication-related osteonecrosis of the jaw (MRONJ). This case illustrates a patient with metastatic breast cancer (MBC) who developed recurrent, severe hypercalcemia after discontinuing denosumab due to MRONJ, followed by profound hy

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… Over the subsequent years, her regimen was adjusted to include pertuzumab during periods of disease progression and fulvestrant for further endocrine blockade, and later, Kadcyla (T-DM1) and trastuzumab-deruxtecan as newer HER2-targeted agents became indicated. … - | - | - | - 6/2013 | - a | 8.9 | - | - | - | - | - | - 9/2013 | Monthly denosumab (Xgeva) started | - | - | - | - | - | - | - 1/2014 | - | 9 | - | - | - | 3 | - | - 6/2014 | Discontinued trastuzumab & pertuzumab | - | - | - | - | - | - | - 8/2014 | - | 8.9 | - | - | - | - | - | - 9/2014 | Monthly fulvestrant …

A Comparison of the Efficacy and Safety of Denosumab and Zoledronic Acid in Patients with Bone Metastatic Breast Cancer Receiving CDK4/6 Inhibitor Therapy.

Background and Objectives: Bone metastases in patients can cause significant quality-of-life declines due to skeletal-related events (SREs). SRE is defined as the occurrence of radiotherapy for bone pain, pathologic fracture, bone surgery, spinal cord compression, or hypercalcemia. Bone-modifying agents (BMAs), such as denosumab and zoledronic acid, are crucial in reducing the frequency and severity of SREs. The inhibition of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has emerged as the standard treatment for hormone receptor-positive metastatic breast cancer, demonstrating significant im

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… 0.108 Yes | 134 (40.9%) | 66 (36.9%) | 68 (45.6%) No | 194 (59.1%) | 113 (63.1%) | 81 (54.4%) CDK4/6 inhibitors | 0.307 Ribociclib | 197 (60.1%) | 103 (57.5%) | 94 (63.1%) Palbociclib | 131 (39.9%) | 76 (42.5%) | 55 (36.9%) Endocrine agent | 0.523 Letrozole | 226 (68.9%) | 126 (70.4%) | 100 (67.1%) Fulvestrant … 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. 2017;35:2875–2884. doi: 10.1200/JCO.2017.73.7585. 17. …

Therapeutic Advances in Oncology.

Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment

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… Faslodex (fulvestrant) is another agent that is approved for HR-positive postmenopausal women with disease progression that had previously received other anti-estrogen therapy. Fulvestrant therapy results in ER degradation, therefore, halts ER signaling. … Two novel therapies for endocrine resistance metastatic breast cancer include Capivasertib (AZD5363) in combination with fulvestrant and Histone deacetylase (HDAC) inhibitor in combination with exemestane. …

Network approach in liquidomics landscape.

Tissue-based biopsy is the present main tool to explore the molecular landscape of cancer, but it also has many limits to be frequently executed, being too invasive with the risk of side effects. These limits and the ability of cancer to constantly evolve its genomic profile, have recently led to the need of a less invasive and more accurate alternative, such as liquid biopsy. By searching Circulating Tumor Cells and residues of their nucleic acids or other tumor products in body fluids, especially in blood, but also in urine, stools and saliva, liquid biopsy is becoming the future of clinical

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… Primary objective of the therapeutic randomized phase is to assess whether palbociclib plus fulvestrant improves relapse-free survival compared to standard of care adjuvant endocrine therapy in patients with detectable ctDNA in the plasma but without evidence of metastatic disease on imaging. …

Relationship between Medication-Related Osteonecrosis of the Jaw and CDK4/6 Inhibitors in Breast Cancer.

OBJECTIVE: We aimed to evaluate the use of CDK4/6 inhibitors as a risk factor for medication-related osteonecrosis of the jaw (MRONJ) in a cohort of patients with metastatic breast cancer treated with denosumab. METHODS: This was a multicentre, retrospective, observational study. All patients with breast cancer treated with denosumab (January 2011-December 2022) were included. The relationship between CDK4/6 inhibitors and MRONJ was analysed. RESULTS: A total of 243 patients were included, ninety-five (44.2%) of whom used a CDK4/6 inhibitor. There were 21 patients with MRONJ. In patients tre

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… Palbociclib was used at a dosage of 125 mg per day in combination with an aromatase inhibitor or fulvestrant. In cases of toxicity, the doses were reduced based on indications in the technical data sheets. … MONARCH 2: Abemaciclib in Combination with Fulvestrant inWomen with HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J. Clin. Oncol. 2017;35:2875–2884. doi: 10.1200/JCO.2017.73.7585. 33. …

Effect of the national reimbursement drug list negotiation policy on utilization of negotiated anticancer drugs in Chinese public hospital: a quasi-natural experiment.

BackgroundHigh prices have limited access to targeted anticancer drugs in China. In 2017, 18 such drugs were added to the National Reimbursement Drug List (NRDL) through national price negotiation.MethodMonthly hospital procurement data (2015-2019) from 887 public hospitals across 30 provinces were analyzed. Drug utilization was measured by expenditures and defined daily doses (DDDs). A difference-in-differences (DID) model and interrupted time series (ITS) analysis were employed to estimate policy effects.ResultsFollowing policy implementation, total DDDs of negotiated drugs rose 4.03-fold an

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… Protein kinase inhibitors and endocrine therapies (e.g., Abiraterone, Fulvestrant) also showed substantial upward trajectories. … Trastuzumab again showed the highest growth in DDDs (+53.07 ten thousand), followed by Fulvestrant (+29.40 ten thousand) and Bevacizumab (+29.30 ten thousand). …

PI3K/AKT сигнализирующий путь: молекулярный перекресток в опухоли и терапевтические инновации.

PI3K/AKT сигнализирующий путь служит центральным регулирующим узлом, регулирующим основные клеточные процессы, включая рост, распространение, метаболизм, выживание и миграцию. В контексте развития опухоли и рака аберральная активация этого пути приводит к злокачественным преобразованиям, усиливает инвазивный и метастатический потенциал и оказывает сопротивление терапевтическому вмешательству, что в конечном счете приводит к прогрессированию опухоли и более низким клиническим результатам. В этом исследовании всесторонне изучается ИП3К/АКТ, сигнализирующий о его причастности к различным человече

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… is also undergoing a global, multicenter phase III clinical trial ( NCT04338399 ) in combination with paclitaxel for HNSCC, with approval from the Food and Drug Administration (FDA). 417 Preclinical studies demonstrated tumor regression in estrogen receptor-positive BC xenografts when combined with fulvestrant … Inavolisib (GDC0077), an orally administered inhibitor targeting PI3Kα, is currently under evaluation in a phase III clinical trial ( NCT04191499 ) to assess its efficacy in combination with palbociclib and fulvestrant for HR-positive, HER2-negative BC harboring PIK3CA mutations. 425 Alpelisib (BYL719 …