The journey of patients affected by metastatic hormone receptor-positive/HER2-negative breast cancer from CDK 4/6 inhibitors to second-line treatment: a real-world analysis of 701 patients enrolled in the GIM14/BIOMETA study

European Journal of Cancer, Год журнала: 2024, Номер 213, С. 115113 - 115113

Опубликована: Ноя. 4, 2024

Язык: Английский

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Oral selective estrogen receptor degraders for breast cancer treatment: focus on pharmacological differences

Breast Cancer Research and Treatment, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

Язык: Английский

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Targeting CDK4/6 in breast cancer

Experimental & Molecular Medicine, Год журнала: 2025, Номер unknown

Опубликована: Фев. 10, 2025

Abstract Dysregulation of the cell cycle machinery, particularly overactivation cyclin-dependent kinases 4 and 6 (CDK4/6), is a hallmark breast cancer pathogenesis. The introduction CDK4/6 inhibitors has transformed treatment landscape for hormone receptor-positive by effectively targeting abnormal progression. However, despite their initial clinical success, drug resistance remains significant challenge, with no reliable biomarkers available to predict response or guide strategies managing resistant populations. Consequently, numerous studies have sought investigate mechanisms driving optimize therapeutic use improve patient outcomes. Here we examine molecular regulating cycle, current applications in cancer, key contributing resistance. Furthermore, discuss emerging predictive highlight potential directions overcoming enhancing efficacy.

Язык: Английский

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Efficiency of Fulvestrant Monotherapy After CDK4/6 Inhibitor Exposure: Is This a Viable Choice?

Cancers, Год журнала: 2025, Номер 17(5), С. 884 - 884

Опубликована: Март 4, 2025

Guidelines for the first-line treatment of Hormone Receptor-positive, HER2-negative advanced or recurrent breast cancer have shifted to combination therapies a CDK4/6 inhibitor and endocrine therapy. However, determining an optimal subsequent therapy following progression remains challenging, especially tumors lacking actionable mutations. Real-world data suggest that fulvestrant monotherapy is frequently selected in this post-CDK4/6 setting. This review examines its therapeutic potential evolving landscape. A systematic literature search using PubMed ClinicalTrials.gov identified 153 clinical trials published between 2017 November 2024, from which ten studies met our strict inclusion criteria, focusing solely on monotherapy. These encompassed 1038 patients who had prior exposure inhibitors. The were categorized into three groups: (EMERALD, SERENA-2, AMEERA-3, ELAINE-1), (CAPItello-291 VERONICA), rechallenge (post-MONARCH, PACE, PALMIRA, MAINTAIN). median progression-free survival was 3.18 months (range 1.9–5.3 months). Factors affecting efficacy second-line include treatments, duration, genetic Given short-lived second lines, participating vital option until novel alternative choice becomes available.

Язык: Английский

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Preclinical evaluation of a novel antibody–drug conjugate OBI-992 for Cancer therapy

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 13, 2025

Trophoblast cell surface antigen 2 (TROP2), a transmembrane glycoprotein highly expressed in variety of epithelial cancers, has been considered as primary therapeutic target for the development antibody–drug conjugates (ADCs). OBI-992, an investigational TROP2-targeted ADC, is composed novel TROP2 antibody (R4702) conjugated to topoisomerase I (TOP1) inhibitor exatecan through hydrophilic enzyme-cleavable linker. This study aimed characterize R4702 and OBI-992 vitro. antibodies sacituzumab datopotamab were employed comparators R4702. ADCs govitecan (SG) deruxtecan (Dato-DXd) used benchmarks OBI-992. Results revealed that binds epitope distinct from datopotamab. The cytotoxicity SG, Dato-DXd against different cancer cells comparable despite they have internalization profile. Upregulation breast resistance protein (BCRP) was observed SG-resistant Dato-DXd-resistant cells, but not OBI-992-resistant cells. In addition, significant downregulation expression detected with only slightly SG- observed. Moreover, substantial enhancement DNA damage found combination poly (ADP-ribose) polymerase (PARP) (talazoparib). Taken together, findings this support further clinical

Язык: Английский

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Oral selective estrogen receptor degraders (SERDs) in Hormone receptor-Positive HER2-Negative Metastatic breast cancer After Progression with CDK4/6 inhibitors

Expert Review of Anticancer Therapy, Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

Hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (mBC) remains a prevalent and challenging disease. Endocrine therapy (ET) combined with CDK4/6 inhibitors is the first-line standard of care, yet resistance mechanisms, including ESR1 mutations, drive disease progression. Novel oral selective estrogen receptor degraders (SERDs) have emerged as promising therapeutic agents after progression secondary to mutations. However, available studies on SERDs differ in design, study population, outcomes, necessitating critical review data. This explores clinical efficacy, safety profiles HR-positive, mBC, particularly following inhibitors. Recent key trials, EMERALD, SERENA-2, EMBER-3 AMEERA-3, are analyzed, highlighting their efficacy overcoming resistance, especially ESR1-mutant populations. Oral offer enhanced bioavailability convenience compared fulvestrant, representing advancement endocrine therapy. Their integration into treatment strategies, combination regimens ctDNA-driven approaches, may improve patient outcomes address mechanisms. other than refinement for selection limited. Further trials needed optimize SERD use define most effective strategies SERDs.

Язык: Английский

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Post-Progression treatment options after CDK4/6 inhibitors in hormone Receptor-Positive HER2-Negative metastatic breast cancer

Cancer Treatment Reviews, Год журнала: 2025, Номер unknown, С. 102924 - 102924

Опубликована: Март 1, 2025

Язык: Английский

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Molecular Mechanisms and Therapeutic Strategies to Overcome Resistance to Endocrine Therapy and CDK4/6 Inhibitors in Advanced ER+/HER2− Breast Cancer

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(7), С. 3438 - 3438

Опубликована: Апрель 7, 2025

Approximately 70-80% of breast cancers are estrogen receptor-positive (ER+), with 65% these cases also being progesterone (ER+PR+). In most ER+ advanced cancer, endocrine therapy (ET) serves as the first-line treatment, utilizing various drugs that inhibit ER signaling. These include tamoxifen, a selective receptor modulator (SERM); fulvestrant, degrader (SERD); and aromatase inhibitors (AIs), which block synthesis. However, intrinsic or acquired hormone resistance eventually develops, leading to disease progression. The combination ET cyclin-dependent kinase 4 6 (CDK4/6is) has been shown significantly increase progression-free survival (PFS) and, in some cases, overall (OS). CDK4/6is works by arresting cell cycle G1 phase, preventing DNA synthesis, enhancing efficacy ET. This review highlights key mechanisms ET, whether used alone biological agents, well emerging therapeutic strategies aimed at overcoming resistance. Addressing remains work progress, near future, better patient selection for different approaches is expected through identification more precise genetic markers. particular, liquid biopsy may provide real-time portrait disease, offering insights into driving cancer

Язык: Английский

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Detection of ESR1 Mutations in Tissue and Liquid Biopsy with Novel Next-Generation Sequencing and Digital Droplet PCR Assays: Insights from Multi-Center Real Life Data of Almost 6000 Patients

Cancers, Год журнала: 2025, Номер 17(8), С. 1266 - 1266

Опубликована: Апрель 9, 2025

Background: ESR1 mutations are biomarkers in breast cancer patients who develop metastatic disease after endocrine therapy (ET). Recently, the Food and Drug Administration (FDA) European Medicines Agency (EMA) have approved Elacestrant, a selective estrogen receptor degrader for harboring mutations. This has necessitated establishment of reliable sensitive NGS- or PCR-based assays to detect these resistance liquid biopsy samples. Methods: We evaluated NGS results pan-cancer cohort almost 6000 from two major German institutes pathology, show that occurrence is extremely rare (<1%) ET-naïve patients. suggests arise exclusively under pressure ET. Therefore, we designed cancer-specific hybrid capture-based assay covering 12 cancer-related genes, including ESR1, PIK3CA, AKT1, ERBB2, BRCA1/2, TP53. validated HS2-Mamma-LIQ extensively using reference material 0.1% variant allele frequency (VAF) compared performance commercially available ddPCR assay. Results: routine diagnostic analysis first consecutive 354 with activating rate 43%, 20% co-mutations PIK3CA other genes underlining relevance tumor heterogeneity. Our study highlights as preferred approach monitoring by showing cases where complex heterogeneity multiple well at different VAFs. Conclusions: findings not only corroborate prior research concerning rarity unselected but also emphasize importance robust broad molecular rather than single gene their detection characterization setting. Advantages approaches discussed address current clinical need.

Язык: Английский

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Second-Line Endocrine Therapy With or Without Palbociclib Rechallenge in Patients With Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: PALMIRA Trial

Journal of Clinical Oncology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 28, 2025

PURPOSE Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors plus endocrine therapy (ET) represents the standard first-line treatment for patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HER2-negative) advanced breast cancer (ABC). However, there is no definitive consensus on preferred second-line option. The PALMIRA trial investigated whether palbociclib rechallenge an alternative ET would improve antitumor activity in progressing after a palbociclib-containing regimen. METHODS This international, randomized, open-label, phase II study enrolled 198 receptor–positive/HER2-negative ABC disease progression (aromatase inhibitor or fulvestrant). Patients were eligible if they showed clinical benefit to previous regimen (response stable ≥24 weeks) had progressed palbociclib-based adjuvant setting. randomly assigned (2:1 ratio) either (fulvestrant letrozole) alone. Stratification factors visceral involvement. primary end point was investigator-assessed progression-free survival (PFS). RESULTS Between April 2019 October 2022, 136 62 alone, respectively. Median PFS 4.9 months (95% CI, 3.6 6.1) versus 2.5 4.2) alone (hazard ratio, 0.84 [95% 0.66 1.07]; P = .149). Grade ≥3 treatment-emergent adverse events higher (47.4% v 10.0%), without new safety signals. CONCLUSION Palbociclib did not significantly compared

Язык: Английский

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