Search Results (252)

Background/Objectives: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are commonly used as first-line treatment for hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. However, the optimal timing of CDK4/6i initiation remains uncertain. This study compared overall survival (OS) between upfront first-line and deferred second-line CDK4/6i use in routine clinical practice. Methods: This retrospective, two-center cohort study included 403 patients with hormone receptor-positive, HER2-negative metastatic breast cancer who received a CDK4/6i between January 2019 and December 2024. Patients were categorized into upfront-use and deferred-use groups according to whether CDK4/6i treatment was initiated in the first or second metastatic treatment line. Overall survival was estimated using the Kaplan–Meier method. An exploratory analysis of progression-free survival (PFS) from CDK4/6i initiation was also performed. Cox proportional hazards regression, inverse probability of treatment weighting (IPTW), and a 12-month landmark analysis were performed. Results: Of 403 patients, 311 received upfront treatment and 92 received deferred treatment. At a median follow-up of 63.0 months, the deferred-use group had higher rates of visceral metastasis and endocrine-resistant disease. Median PFS from CDK4/6i initiation was longer in the upfront-use group than in the deferred-use group (27.0 vs. 14.0 months; log-rank p < 0.001). Median OS was 61.0 months in the upfront-use group and 76.0 months in the deferred-use group, without a statistically significant difference (log-rank p = 0.059). After adjustment for clinical factors and year of metastatic diagnosis, deferred use was not independently associated with OS (adjusted hazard ratio [HR] 1.167, 95% confidence interval [CI] 0.772–1.765, p = 0.463). Similar results were obtained in the IPTW analysis (HR 0.925, 95% CI 0.552–1.549; p = 0.766) and the 12-month landmark analysis. Conclusions: Deferred second-line CDK4/6i use was not independently associated with inferior overall survival compared with upfront use. These findings support an individualized, risk-adapted sequencing approach in carefully selected patients but do not establish equivalence or justify routine deferral. Full article

Background/Objectives: Cyclin-dependent kinase 2 (CDK2) is a key regulator of cell-cycle progression and a potential anticancer target. This study aimed to identify alkaloid-derived CDK2 ligands using an integrated computational workflow and to obtain preliminary evidence of their effects on cancer-cell viability. Methods: Molecular docking with mVina and fast pulling of ligand (FPL) simulations were benchmarked using 20 experimentally characterized CDK2 inhibitors. A library of 2692 PubChem-derived alkaloids was screened, followed by ADMET evaluation, 100 ns molecular dynamics simulations, and FPL-based relative-affinity re-ranking. The three prioritized compounds were evaluated in HepG2 and HGC-27 cells using an MTT assay after 48 h of exposure. Results: Docking and FPL showed correlations with experimental affinity data of R_Dock = 0.549 ± 0.180 and R_W = −0.676 ± 0.119, respectively. CID 636885, CID 46184320, and CID 101691758 were prioritized for detailed evaluation. All three compounds reduced cell viability, with lower IC₅₀ values observed in HepG2 cells than in HGC-27 cells. CID 101691758 exhibited the highest growth-inhibitory activity among the tested compounds, with IC₅₀ values of 15.37 ± 0.46 µg mL⁻¹ in HepG2 cells and 52.64 ± 1.33 µg mL⁻¹ in HGC-27 cells. Conclusions: The workflow identified three preliminary alkaloid hits, with CID 101691758 showing the most favorable combined computational and cell-viability profile. However, the MTT assay does not establish direct CDK2 inhibition or kinase selectivity. Biochemical CDK2 inhibition, target-engagement, and kinase-panel studies are therefore required. Full article

Breast cancer remains one of the most prevalent malignancies affecting women worldwide and continues to be a leading cause of cancer-related morbidity and mortality. Patients may present with either localized or advanced disease, with clinical outcomes increasingly influenced by molecular subtype and genetic profile. This review highlights the key genetic factors involved in breast cancer, current diagnostic and therapeutic strategies, and promising emerging approaches that may shape future clinical management. Breast cancer diagnosis typically involves clinical breast examination, imaging techniques such as mammography and ultrasound, and confirmatory biopsies. Genetic mutations in specific genes are strongly linked to the development, progression, and metastasis of the disease. Treatment options for localized breast cancer continue to include surgery (lumpectomy or mastectomy) and radiotherapy, combined with systemic therapies tailored to tumor biology, such as endocrine therapy, human epidermal growth factor receptor 2 (HER2)-targeted therapy, and cyclin-dependent kinase (CDK)4/6 inhibitors. For advanced or metastatic breast cancer, recent therapeutic advances include the use of immunotherapy (e.g., immune checkpoint inhibitors), Poly (ADP-ribose) polymerase (PARP) inhibitors for Breast Cancer gene (BRCA)-mutated cancers, antibody–drug conjugates, and novel targeted agents, which have significantly improved patient outcomes in selected populations. Recent findings in breast cancer genetics have highlighted the critical role of germline and somatic mutations, particularly in genes such as BRCA1, BRCA2, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and TP53, in driving tumor initiation, progression, and therapeutic response. Molecular profiling and next-generation sequencing technologies have enabled more precise tumor classification and facilitated the development of personalized treatment strategies. Despite these advances, treatment resistance and disease recurrence remain major challenges, particularly in aggressive subtypes such as triple-negative breast cancer. Consequently, ongoing research is exploring alternative and complementary approaches, including nanotechnology-based drug delivery systems, gene editing techniques such as clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-associated protein 9) (CRISPR-Cas9), cancer vaccines, and the integration of traditional and plant-derived compounds. These strategies aim to enhance therapeutic efficacy, reduce systemic toxicity, and overcome resistance mechanisms. Full article

Cerebellar climbing fiber–Purkinje cell (CF–PC) long-term depression (LTD) plays a critical role in motor learning and is modulated by locus coeruleus (LC) noradrenergic afferents via distinct adrenergic receptor (AR) subtypes. Nevertheless, the mechanisms underlying LC noradrenergic neuron-mediated regulation of CF–PC LTD remain poorly understood. Here, we investigated the effects of chemogenetic activation of LC noradrenergic afferents on CF–PC LTD in cerebellar slices from dopamine β-hydroxylase (DBH)-Cre mice using electrophysiology, glutamate sensor imaging, immunofluorescence and pharmacological approaches. Tetanic stimulation (5 Hz) of CFs induced CF–PC LTD under control conditions, and this LTD was enhanced by chemogenetic activation of LC noradrenergic afferents. Blockade of group I metabotropic glutamate receptors (mGluR1) abolished LTD under control conditions, whereas chemogenetic activation of LC noradrenergic afferents triggered a novel form of CF–PC LTD accompanied by an increased N2/N1 ratio. With mGluR1 blocked, chemogenetic activation of LC noradrenergic afferents failed to trigger the novel CF–PC LTD following blockade of α₂-AR or α₂A-AR, but not α₂B-AR or α₂C-AR. Importantly, chemogenetic activation of LC noradrenergic afferents triggered LTD of glutamate fluorescence at CF terminals, which was abolished by blockade of α_2-AR or α₂A-AR, but not α₂B-AR or α₂C-AR. Notably, inhibition of either cyclin-dependent kinase 5 (CDK5) or presynaptic, but not postsynaptic, protein kinase A (PKA) completely abolished the CF–PC LTD triggered by chemogenetic activation of LC noradrenergic afferents in mouse cerebellar slices. Immunofluorescence results showed robust α₂A-AR expression throughout the cerebellar molecular layer, with intense signals along PC dendrites and clear colocalization with vesicular glutamate transporter 2 (vGluT2) at cerebellar CF terminals. These results indicate that activation of LC noradrenergic afferents potentiates CF–PC LTD by triggering Glu-LTD at CF terminals through the α₂A-AR/CDK5/PKA signaling cascade in the mouse cerebellar cortex. Full article

Chemotherapy resistance remains a major challenge in colorectal cancer (CRC) treatment, necessitating novel adjuvant strategies. This study employed an integrated analytical strategy combining network pharmacology, single-cell RNA sequencing (scRNA-seq) of patient-derived organoids (PDOs) and molecular dynamics simulations to identify bioactive compounds from Ganoderma lucidum and elucidate their chemo-sensitizing mechanisms. Network pharmacology identified five bioactive components of G. lucidum, corresponding to 267 potential targets. Integration with transcriptomic data, weighted gene co-expression network analysis (WGCNA), and known CRC genes refined these to 19 core targets. Cross-referencing with scRNA-seq data from irinotecan-treated PDOs pinpointed cyclin-dependent kinase 2 (CDK2) and Aurora kinase A (AURKA) as pivotal targets. Molecular dynamics simulations confirmed stable binding of the key component cerevisterol to both CDK2 and AURKA proteins, with binding free energies of −120.67 kJ/mol and −134.47 kJ/mol, respectively. In vitro cell viability assays across multiple CRC cell lines (HCT116, RKO, and HT-29) and PDOs demonstrated that cerevisterol significantly sensitized CRC cells to irinotecan (SN38). Notably, we observed that CDK2 was preferentially enriched in MSI-H tumors, whereas AURKA was enriched in MSS tumors, suggesting the potential of MSI status as a biomarker for patient stratification. Collectively, these findings identify cerevisterol as a dual-targeting natural product that modulates CDK2 and AURKA to overcome chemotherapy resistance, providing a quantitative analytical framework for discovering bioactive compounds and their molecular targets from medicinal fungi. Full article

Background: Cyclin-dependent kinase 2 (CDK2) is a key regulator of cell cycle progression and an important therapeutic target in cancer treatment. This study aims to identify novel CDK2 inhibitors using an integrated computational approach combining machine learning and structure-based methods. Methods: A computational pipeline was developed incorporating Lipinski’s Rule of Five filtering, machine learning (ML)-based activity prediction, molecular docking, and molecular dynamics simulations (MDs). A dataset of CDK2 inhibitors with IC50 values was retrieved from ChEMBL, and molecular fingerprints were generated using PaDEL. A 5-fold stratified cross-validation approach was applied to train multiple classifiers, with the random forest model showing the best performance. Predicted active compounds from the InterBioScreen database were subjected to docking against CDK2 (PDB ID: 2FVD) using PyRx, followed by 100 ns MDS for stability analysis. Results: The random forest classifier achieved an AUC-ROC of 0.90 and an accuracy of 0.84. A total of 187 compounds were predicted as active. Among these, two compounds, STOCK4S-00019 and STOCK4S-00025, demonstrated docking scores comparable to the co-crystallized reference ligand. Molecular dynamics simulations confirmed stable binding, consistent interaction patterns, and favorable conformational behavior throughout the simulation period. Conclusions: The identified compounds, STOCK4S-00019 (hit1) and STOCK4S-00025 (hit2), show strong potential as CDK2 inhibitors. These findings support their further investigation through experimental validation and highlight the effectiveness of integrated computational approaches in anticancer drug discovery. Full article

Background/Objectives: Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Despite advances in treatment, outcomes for advanced CRC remain unsatisfactory due to uncontrolled proliferation, metastasis, and recurrence. This study investigated the anti-cancer effects of KMU-11342, an indolin-2-one-based multi-protein kinase inhibitor with previously reported anti-inflammatory properties, in human colorectal cancer models. Methods: The anti-cancer effects of KMU-11342 were evaluated in colorectal cancer cells and further investigated in three-dimensional (3D) spheroid and patient-derived organoid models. Cell proliferation, migration, apoptosis, and cell cycle progression were assessed. Kinase activity profiling and molecular docking analyses were performed to identify potential targets and characterize the underlying signaling pathways. Results: KMU-11342 significantly inhibited the proliferation and migration of CRC cells. It reduced CRC cell density by 58.9% and 83.3% at 0.5 and 1 μM, respectively. These effects were accompanied by G2/M cell cycle arrest and apoptotic cell death. In 3D models, spheroid formation was markedly reduced and stemness-related characteristics were diminished. Patient-derived CRC organoids also showed decreased viability, exhibiting 38.6% and 77.4% reductions at 1 and 2 μM, respectively. These effects were observed in a dose-dependent manner in both two-dimensional (2D) and 3D colorectal cancer models. Kinase activity profiling and molecular docking analyses identified glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase 1 (CDK1) as potential mediators of the anti-cancer effects of KMU-11342 through the p53/nuclear factor kappa B (NF-κB) and FoxO1 signaling axes, respectively. Conclusions: KMU-11342 exhibits potent anti-tumor activity against CRC through suppressing proliferation, migration, and stemness in both 2D and 3D models, including patient-derived organoids. Its effects may be mediated, at least in part, through modulation of GSK3β and CDK1 via the p53/NF-κB and FoxO1 signaling pathways. Full article

Background/Objectives: Advanced hormone receptor-positive (HR+), epidermal growth factor 2-negative (HER2−) breast carcinoma (BC) patients receive frontline therapy with cyclin-dependent tyrosine kinase 4/6 inhibitors + endocrine therapy (ET). At progression, the best management includes mutational analysis for ESR-1, allowing second-line therapy with elacestrant. The aim of this study was to evaluate the efficacy and safety of elacestrant in an Italian real-world setting. Methods: A multicenter, observational study with a mixed retrospective and prospective design was conducted in 13 medical oncology units across Italy. The study population included adult patients with HR+/HER2− locally advanced or metastatic breast cancer with an activating ESR1 mutation documented by liquid biopsy and progressing after at least one line of endocrine therapy containing a CDK4/6 inhibitor. Mutational analysis of plasma was performed using next-generation sequencing with a multigene panel that included ESR1, PIK3CA, AKT, and PTEN. The sample size was calculated according to the two-stage Simon design. Toxicity was classified according to CTCAE version 5.0 criteria. Survival analyses were conducted using the Kaplan–Meier method. Results: At the time of analysis, 39 evaluable patients were enrolled, all female and Caucasian, with a median age of 67 years (range 41–89). The efficacy analysis documented an overall ORR of 28% and a disease control rate of 56%. The median duration of response was 6+ months (95% CL: 3.5–10.6 m). Median overall survival was not reached with a median follow-up of 10 months. The toxicity profile was overall favorable: grade ≥2 asthenia was the most frequent adverse event (23%), followed by gastrointestinal toxicity, which was generally mild. No treatment-related toxicity was reported in 64% of patients. Dose reductions were necessary in 15% of cases, while permanent treatment discontinuation due to toxicity occurred in only 4%. Conclusions: The results of this Italian multicenter observational study confirm the efficacy and tolerability of elacestrant in HR+/HER2− metastatic breast cancer with ESR1 mutation, in a real-world context consistent with the data from the pivotal EMERALD study and with real-world data present in the literature. Full article

Introduction: In the treatment of hormone receptor-positive (HR+), HER2-negative (HER2−) metastatic breast cancer (MBC), the current guidelines recommend endocrine therapy combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors as the preferred first-line treatment to preserve quality of life. Ribociclib is a CDK4/6 inhibitor that has been used in combination with aromatase inhibitors or fulvestrant in patients with HR+, HER2− metastatic breast cancer. Various adverse drug reactions associated with ribociclib have been reported, including cutaneous reactions, hepatotoxicity, and hematologic toxicity. In this study, we aimed to evaluate the clinical manifestations and risk factors of dermatologic toxicities in patients with metastatic breast cancer treated with ribociclib. Methods: This retrospective study included patients with metastatic/recurrent breast cancer who were prescribed ribociclib from April 2021 to December 2024 at a single institution. We retrospectively reviewed the medical records of these patients to identify the frequency of cutaneous adverse events, the time of onset, and the clinical characteristics of skin reactions. Logistic regression analysis was performed on several clinical factors, including body surface area (BSA) and concomitant medications, to identify risk factors associated with the occurrence of cutaneous adverse events. Results: A total of 110 patients with MBC were enrolled during the study period. The median age was 53 years (range, 28–82); all 110 patients (100.0%) were female; the median BSA was 1.56 m² (range, 1.29–2.07); and 32 patients (29.1%) were premenopausal. Ribociclib plus letrozole was administered in 48 patients (43.6%) and ribociclib plus fulvestrant in 29 patients (26.4%). An additional 33 patients (30.0%) received ribociclib plus letrozole with a gonadotropin-releasing hormone (GnRH) agonist. Cutaneous adverse events occurred in 29 patients (26.4%), and the median time to onset was 84 days (range, 3–498). The cutaneous adverse event patterns included pruritus, erythematous macular rash, eczematous rash/contact dermatitis, vitiligo, urticarial reactions, polymorphous light eruption, toxic epidermal necrolysis (TEN), and desquamation. Grade 1 or 2 cutaneous adverse events occurred in 93.1% of patients; Grade 3 toxicity occurred in one patient; and Grade 4 toxicity, namely toxic epidermal necrolysis (TEN), was reported in one patient. Dose reduction was required in three patients (10.3%), and permanent discontinuation of ribociclib occurred in one patient. Clinical improvement was achieved in the majority of patients (86.2%) with cutaneous adverse events following supportive care. Logistic regression analysis revealed that age, Eastern Cooperative Oncology Group (ECOG) performance status, body surface area (BSA), treatment regimen, and use of cholesterol-lowering medications were not independently associated with the development of cutaneous adverse events. Conclusion: CDK4/6 inhibitors represent one of the most important treatment options for HR+/HER2− metastatic breast cancer. Regardless of their clinical efficacy, cutaneous adverse events remain a common source of patient discomfort. Therefore, careful clinical attention and appropriate supportive care are essential to improve patients' quality of life. Full article

The oncogenic Marek’s disease virus (MDV) triggers Marek’s disease (MD), which is a substantial threat to poultry as it transforms infected T cells into tumors. Our research identified that long non-coding RNA 9802 (lncRNA-9802) exhibits increased expression in the chicken spleen following MDV infection, with its expression being strongly associated with the expression of tumor p53-binding protein 1 (TP53BP1). The function of lncRNA-9802 in T cells transformed by MDV remains unclear. Consequently, the expression levels of lncRNA-9802 were either over-expressed or knocked down in MDV-transformed T cells, MDCC-MSB1, through lentivirus-mediated over-expression and knock down experiments. Our findings demonstrate that lncRNA-9802 induces proliferation disturbances in MDCC-MSB1 cells by causing arrest in the S phase, which is accompanied by increased expression levels of TP53BP1, p53, and p21. Activation of the p53 pathway results in elevated levels of Cyclin E and Cyclin-dependent kinase 2 (CDK2), thereby facilitating the entry of MDCC-MSB1 cells into the S phase. Concurrently, the reduced levels of Cyclin A inhibit the exit of MDCC-MSB1 cells from the S phase. By modulating the TP53BP1/p53/p21 pathway, lncRNA-9802 induces S phase arrest in MDCC-MSB1 cells, characterized by upregulation of Cyclin E and CDK2 and downregulation of Cyclin A. This research enhances the understanding of the pathogenic mechanisms of MDV and provides a foundation for identifying potential targets for antiviral drug development. Full article

Background: Evaluation of gene-level copy number variants (CNVs) for diagnosis and therapeutic decision making has become standard of care with next-generation sequencing (NGS), immunohistochemistry (IHC), and/or fluorescence in situ hybridization (FISH) being used to detect gene amplifications/deletions in tumor tissue. In contrast to most solid tumors, CNS cancers are challenging to evaluate by resection and/or biopsy due to the associated risks with invasive brain surgery that can also result in death or associated morbidity and therefore alternate methods are required.Methods: This study presents the analytical validation of using quantitative PCR (qPCR) to detect gene CNVs directly from cerebrospinal fluid (CSF)-derived DNA and from the Ascent^TM low-pass whole genome sequencing (LP-WGS) libraries, demonstrating concordance with the gold standard of NGS/IHC/FISH used in tumor tissue. Results: The analytical sensitivity of qPCR to detect gene amplification calls for ERBB2 (erb-b2 receptor tyrosine kinase 2) was demonstrated to be 100% and that of EGFR (epidermal growth factor receptor) was 83%, with specificities of 96% and 100%, respectively. The analytical sensitivity of qPCR to detect gene deletions for CDKN2A/2B (cyclin-dependent kinase inhibitor 2A/2B) was 60% and that for MTAP (methylthioadenosine phosphorylase) was 100% with a specificity of 100% for all three genes. Ascent^TM was demonstrated to have a higher sensitivity (100%) when compared to qPCR for the same genes evaluated and demonstrated 100% positive agreement and 100% negative agreement with known CNV status. Conclusions: The results demonstrate that given the paucity of cells in CSF limiting the use of IHC and FISH, qPCR and Ascent^TM provide highly sensitive, novel, minimally invasive methods for the evaluation of gene copy number (CN) status to inform the diagnosis and management of CNS cancers. Full article

The taxane family of compounds, including paclitaxel, docetaxel (Taxotere), and cabazitaxel (Jevtana), are common drugs used in chemotherapy for the frontline treatment of most major types of cancer. Alopecia, the dramatic loss of hair, is a common side effect that became a symbol of the suffering of many cancer patients. Concerted efforts have been made to understand the mechanism of taxane toxicity to hair follicles and, thus, prevention methods. Taxanes act by stabilizing cellular microtubules, which consequently cause mitotic arrest and then failure, as microtubules play critical functions in chromosome segregation. Hair follicle matrix cells are highly proliferative and thus are exceedingly sensitive to taxanes. We review the cellular mechanism-based strategies under investigation to counter taxane-induced hair follicle damage. These include the application of cyclin kinase inhibitors to block mitotic entry, the practical method using scalp cooling to reduce exposure of scalp hair follicles to drugs during infusion, the requirement of p53 action for hair follicle damage, and the recently discovered method of using low-intensity ultrasound to break taxane-stabilized microtubules and thus reverse taxane toxicity in hair follicle matrix cells. The concept of low-intensity ultrasound as an antidote to taxanes may have the potential to provide a practical and compelling strategy to counter alopecia in cancer treatment using taxanes. Tweet: Taxanes (paclitaxel/docetaxel) are powerful microtubule-stabilizing cancer drugs, but they also cause adverse effects, including alopecia. New research discoveries of temporary microtubule disruption by low-intensity ultrasound may counteract taxane toxicity and prevent alopecia during cancer chemotherapy. “Mechanistic-based strategies for the prevention of taxane-induced hair follicle damage in cancer chemotherapy” OUTLINE: 1. Taxane/paclitaxel mechanism of action in cancer therapy. 2. Taxane side effects: Alopecia (hair loss). 3. p53 dependence of taxane-induced hair follicle damage. 4. Research efforts to counter taxane -induced alopecia by CDK4/6i. 5. Prevention of taxane chemotherapy side effects using scalp cooling. 6. Discovery of low-intensity ultrasound as an antidote for taxane cytotoxicity, and potential prevention of alopecia in chemotherapy using taxanes. 7. Summary and prospective. Full article

Background: Hormone receptor-positive (HR+), Human Epidermal growth factor Receptor 2 (HER2-negative) metastatic breast cancer (MBC) represents a substantial proportion of breast cancer cases in Saudi Arabia. Despite the established efficacy of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, particularly Palbociclib, in randomized control trials, real-world data from local institutions in Saudi Arabia remain limited. Objectives: This study aimed to evaluate progression-free survival (PFS), overall survival (OS), and toxicity profile among HR+, HER2-negative MBC female patients treated with Palbociclib at King Fahad Medical City (KFMC). Methods: A retrospective study was conducted on female patients with HR+/HER2-negative MBC treated with oral palbociclib combined with endocrine therapy (ET) at KFMC between January 2021 and September 2024. Data were collected from electronic health records. Descriptive statistics were conducted using mean for continuous variables and frequency for categorical variables. Survival analyses were conducted using Cox regression, log-rank tests and Kaplan–Meier analysis. Results: A total of 169 female patients with HR+/HER2− MBC were included. In the first-line setting, the median PFS was 20.14 months (95% CI: 14.65–30.49), compared with 11.3 months (95% CI: 7.98–not estimable) in the second-line setting. For OS, the median OS values were 53.1 months (95% CI: 41.2–not estimable) in the first-line group and 23.7 months (95% CI: 18.5–not estimable) in the second-line group. Significant predictors of shorter PFS included age, Body Mass Index (BMI), type of ET, cancer type, line of therapy, family history of cancer, and history of VTE. Visceral metastasis (HR = 3.087; p = 0.0229) and ECOG performance status of 4 (HR = 13.86; p = 0.0156) were associated with significantly shorter OS. The most common hematological adverse events (AEs) were neutropenia (45.6%), followed by anemia (5.9%), leukopenia (5.3%), and back pain (5.3%). Most toxicities were managed with dose reduction, holding treatment, or supportive care. Conclusions: Palbociclib demonstrated favorable survival outcomes and a manageable safety profile, with neutropenia being the most common AE. This study provides region-specific real-world evidence supporting the use of Palbociclib in HR+/HER2− MBC. These findings align with global trial data and highlight the importance of individualized treatment in clinical practice. Full article

Background and Objectives: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are recommended as first- or second-line treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or recurrent breast cancer. However, in clinical practice, initiation timing varies according to patient characteristics, prior treatments, and the choice of the physician. Thus, the optimal timing of combination treatment remains unclear. Materials and Methods: In this multicenter retrospective cohort study, we reviewed 66 female patients who received CDK4/6i (palbociclib or abemaciclib) between March 2018 and November 2019. Patients were categorized into the first-line treatment (group A) (n = 21) and second- or subsequent-line treatment (group B) (n = 45) groups. In the latter group, endocrine therapy and/or chemotherapy had been administered previously. Duration of treatment with CDK4/6i (DOT), overall survival (OS), treatment duration of other regimens, and reasons for treatment discontinuation after CDK4/6i treatment were compared between groups. Results: The median DOT was significantly longer in group A than in group B (23 months (95% CI, 8–43) vs. 7 months (95% CI, 3–15); p = 0.015, at log-rank test). OS showed no significant difference between the two groups (p = 0.69, at log-rank test). Conclusions: In patients with HR-positive, HER2-negative advanced or recurrent breast cancer, first-line use of CDK4/6 inhibitors was associated with a significantly longer duration of treatment compared with second- or subsequent-line use. However, no significant difference in OS was observed between patients receiving CDK4/6 inhibitors as first-line or second- or subsequent-line therapy. Full article

Background: The prognostic significance of low-level human epidermal growth factor receptor 2 (HER2) expression in hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer remains unclear, particularly in patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). This study aimed to evaluate the impact of HER2-low status on treatment response and survival outcomes in this setting. Methods: This multicenter retrospective cohort study included patients with HR+/HER2− metastatic breast cancer who received first-line endocrine therapy combined with palbociclib or ribociclib between January 2018 and May 2025. HER2-low tumors were defined as immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization, while HER2-zero tumors were classified as IHC 0. Treatment response, progression-free survival (PFS), and overall survival (OS) were compared between groups using Kaplan–Meier analysis and Cox regression models. Results: A total of 309 patients were analyzed, including 122 (39.5%) with HER2-low disease and 187 (60.5%) with HER2-zero disease. Baseline clinicopathological characteristics were well balanced between groups. The overall response rate was 75.4% in the HER2-low group and 72.7% in the HER2-zero group (p > 0.05). Median PFS was 23.9 months for HER2-low patients and 25.2 months for HER2-zero patients (log-rank p = 0.785). Median OS was 49.5 and 53.1 months, respectively, with no statistically significant difference (log-rank p = 0.649). HER2 status was not an independent predictor of PFS or OS in multivariable analyses. Conclusions: In patients with HR+/HER2− metastatic breast cancer treated with first-line endocrine therapy plus CDK4/6 inhibitors, HER2-low expression was not associated with differences in treatment response or survival outcomes. These findings suggest that HER2-low status does not have prognostic or predictive relevance in this endocrine-sensitive population. Full article