Recent progress of CDK4/6 inhibitors’ current practice in breast cancer

Cancer Gene Therapy, Journal Year: 2024, Volume and Issue: 31(9), P. 1283 - 1291

Published: Feb. 26, 2024

Dysregulated cellular proliferation represents a hallmark feature across all cancers. Aberrant activation of the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway, independent mitogenic signaling, engenders uncontrolled breast cancer cell proliferation. Consequently, advent CDK4/6 inhibition has constituted pivotal milestone in realm targeted therapy. The combination inhibitors (CDK4/6i) with endocrine therapy (ET) emerged as foremost therapeutic modality for patients afflicted hormone receptor-positive (HR + )/HER2-negative (HER2-) advanced cancer. At present, Food Drug Administration (FDA) sanctioned various CDK4/6i employment primary treatment regimen HR /HER2- This approach demonstrated substantial extension progression-free survival (PFS), often amounting to several months, when administered alongside Within this comprehensive review, we systematically evaluate utilization strategies subpopulations explore potential avenues following disease progression during application

Language: Английский

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6th and 7th International consensus guidelines for the management of advanced breast cancer (ABC guidelines 6 and 7)

The Breast, Journal Year: 2024, Volume and Issue: 76, P. 103756 - 103756

Published: May 28, 2024

This manuscript describes the Advanced Breast Cancer (ABC) international consensus guidelines updated at last two ABC conferences (ABC 6 in 2021, virtual, and 7 2023, Lisbon, Portugal), organized by Global Alliance. It provides main recommendations on how to best manage patients with advanced breast cancer (inoperable locally or metastatic), of all subtypes, as well palliative supportive care. These are based available evidence expert opinion when a higher level is lacking. Each guideline accompanied (LoE), grade recommendation (GoR) percentage reached conferences. Updated diagnostic treatment algorithms also provided. The represent management options for living globally, assuming accessibility therapies. Their adaptation (i.e. resource-stratified guidelines) often needed settings where access care limited.

Language: Английский

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Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions

Critical Reviews in Oncology/Hematology, Journal Year: 2024, Volume and Issue: 196, P. 104324 - 104324

Published: March 8, 2024

Aberrant cyclin-dependent kinase 2 (CDK2) activation has been identified as a main resistance mechanism to CDK4/6 inhibition in hormone-receptor positive (HR+) breast cancer. Additionally, consistent preclinical evidence states its crucial role MYC and CCNE1 overexpressed cancer survival, such triple-negative cancers (TNBC), thus representing an appealing relatively unexplored target treatment opportunity. Despite emerging initial results of novel CDK2 inhibitors (CDK2i) activity, comprehensive outcomes collection is currently absent from the scientific literature. We aim provide overview ongoing clinical trials involving CDK2i context metastatic (mBC), either monotherapy or combination with other agents. The review extends beyond encompass CDK4 inhibitors, combined CDK2/4/6 well-known pan-CDK including those specifically directed at CDK2. Delving into results, we critically appraise observed efficacy offer valuable insights their potential impact future applications.

Language: Английский

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Elacestrant in ER+, HER2– MBC with ESR1-mutated tumors: Subgroup Analyses from the Phase III EMERALD Trial by Prior Duration of Endocrine Therapy Plus CDK4/6 Inhibitor and in Clinical Subgroups

Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 30(19), P. 4299 - 4309

Published: Aug. 1, 2024

Abstract Purpose: Elacestrant significantly prolonged progression-free survival (PFS) with manageable safety versus standard-of-care (SOC) endocrine therapy (ET) in patients estrogen receptor–positive (ER+), HER2− metastatic breast cancer and tumors harboring receptor 1 (ESR1) mutation following ET plus a cyclin-dependent kinase 4/6 inhibitor (ET+CDK4/6i). In ESR1-mutated tumors, we evaluated the efficacy of elacestrant SOC based on prior ET+CDK4/6i duration clinical subgroups ≥12 months. Patients Methods: EMERALD, an open-label phase III trial, randomly assigned ER+, who had received 1–2 lines ET, mandatory CDK4/6i, ≤1 chemotherapy to (345 mg daily) or (aromatase fulvestrant). PFS was assessed across post hoc exploratory analyses without adjustment for multiple testing. Results: months, median 8.6 1.9 months (HR, 0.41; 95% confidence interval, 0.26–0.63). this population, (in months) 9.1 (bone metastases), 7.3 (liver and/or lung 9.0 (<3 sites), 10.8 1.8 (≥3 5.5 (PIK3 catalytic subunit α mutation), (tumor protein p53 gene (HER2-low), (ESR1D538G-mutated tumors), (ESR1Y537S/N-mutated tumors). Subgroup consistent overall population. Conclusions: The associated clinically meaningful improvement compared all HER2−, tumors.

Language: Английский

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Circulating tumor DNA validity and potential uses in metastatic breast cancer

npj Breast Cancer, Journal Year: 2024, Volume and Issue: 10(1)

Published: March 12, 2024

Abstract Following the first characterization of circulating tumor DNA (ctDNA) in 1990s, recent advances led to its introduction clinics. At present, European Society Of Medical Oncology (ESMO) recommendations endorse ctDNA testing routine clinical practice for genotyping direct molecularly targeted therapies patients with metastatic cancer. In studies on breast cancer, has been utilized treatment tailoring, tracking mechanisms drug resistance, and predicting disease response before imaging. We review available evidence regarding applications

Language: Английский

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Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer

ESMO Open, Journal Year: 2023, Volume and Issue: 8(3), P. 101541 - 101541

Published: May 11, 2023

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines diagnosis, staging and treatment patients with metastatic breast cancer (MBC) was published in 2021. A special, hybrid guidelines meeting convened by ESMO Korean (KSMO) collaboration nine other Asian national oncology societies May 2022 order to adapt 2021 take into account differences associated MBC Asia. These represent consensus opinions reached a panel experts representing oncological China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Philippines (PSMO), Singapore (SSO), Taiwan (TOS) Thailand (TSCO). voting based on best available scientific evidence independent drug access or practice restrictions different countries. latter were discussed when appropriate. aim these is provide guidance harmonisation management across regions Asia, drawing from data provided global trials whilst at same time integrating genetics, demographics evidence, together restricted certain therapeutic strategies.

Language: Английский

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Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer

npj Breast Cancer, Journal Year: 2023, Volume and Issue: 9(1)

Published: Sept. 8, 2023

Abstract Endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the standard first-line treatment for most patients hormone receptor (HR) positive, human epidermal growth factor (HER2) negative advanced breast cancer. However, resistance to ET and CDK4/6i inevitably ensues. The optimal post-progression regimens their sequencing continue evolve in rapidly changing landscape. In this review, we summarize mechanisms of CDK4/6i, which can be broadly classified as alterations affecting cell cycle mediators activation alternative signaling pathways. Recent clinical trials have been directed at targets pathways implicated, including estrogen androgen receptors, PI3K/AKT/mTOR MAPK pathways, tyrosine receptors such FGFR HER2, homologous recombination repair pathway, other components death. We describe findings from these using small molecule inhibitors, antibody–drug conjugates immunotherapy, providing insights into how novel strategies may circumvent resistance, discuss some not translated benefit. challenges posed by tumor heterogeneity, adaptive rewiring dose-limiting toxicities underscore need elucidate latest biology each patient, develop treatments improved therapeutic index era precision medicine.

Language: Английский

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Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment

Drug Resistance Updates, Journal Year: 2024, Volume and Issue: 76, P. 101103 - 101103

Published: June 25, 2024

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent 6 (CDK6) are key molecules in the G1-to-S phase transition crucial for onset, survival, progression breast (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation tumor suppressor Rb thus restrain susceptible BC cells G1 phase. Three CDK4/6i approved first-line treatment patients with advanced/metastatic hormone receptor-positive (HR

Language: Английский

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Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(10), P. 743 - 761

Published: Aug. 23, 2024

Language: Английский

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Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2− breast tumor cells

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(7)

Published: Feb. 7, 2024

The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor-positive, human epidermal growth factor 2 receptor-negative (ER+/HER2-) breast tumor cells. Despite the drug's success improving patient outcomes, a small percentage of cells continues to divide presence palbociclib-a phenomenon we refer as fractional resistance. It is critical understand cellular mechanisms underlying resistance because precise resistant tissue strong predictor clinical outcomes. Here, hypothesize that arises from cell-to-cell differences core regulators allow subset escape therapy. We used multiplex, single-cell imaging identify fractionally both cultured and primary samples resected patients. Resistant showed premature accumulation multiple G1 including E2F1, retinoblastoma protein, CDK2, well enhanced sensitivity pharmacological inhibition CDK2 activity. Using trajectory inference approaches, show how plasticity among gives rise alternate "paths" individual treatment. Understanding drivers plasticity, eliminate paths, could lead improved cancer therapies targeting improve

Language: Английский

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