BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors marked a milestone in the breast cancer treatment. Due to the potential impact of adverse effects on treatment decisions and patient outcomes, careful consideration of the varying toxicities of CDK4/6 inhibitors is crucial, as three inhibitors-palbociclib, abemaciclib, and ribociclib-have been approved with differences in adverse event profiles. However, limitations in clinical trials call for urgent real-world safety studies to evaluate and compare the risk of adverse events (AEs) among these CDK4/6 inhibitors. Therefore, this study aimed to analyze AEs of CDK4/6 inhibitors and provide insights for clinical drug selection, using real world database.
METHODS: The AEs of CDK4/6 inhibitors in the FDA Adverse Event Reporting System (2015-2022) were analyzed. Four disproportionality methods were used to detect safety signals: reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Neural Network Propagation, and Multi-Item Gamma Poisson Shrinker. Venn analysis was used to compare and select common and specific AEs.
RESULTS: This study included 73,042 patients treated with palbociclib, 25,142 with ribociclib, and 7563 with abemaciclib. All three inhibitors had 27 common AEs. Palbociclib exhibited the highest ROR for hematologic toxicities, while ribociclib showed the highest ROR for macrocytosis, nail disorders, and hepatic lesions. Abemaciclib displayed the highest ROR for mucosal toxicity. Common signals for both palbociclib and ribociclib included hematologic toxicities, decreased immune responsiveness, and aphthous ulcers. Myelosuppression, oral pain, and pseudocirrhosis were common signals for palbociclib and abemaciclib. Anemia, hepatotoxicity, and pneumonitis were observed as common signals for ribociclib and abemaciclib. Furthermore, specific AEs associated with palbociclib included fatigue, alopecia, and stomatitis. For ribociclib, specific AEs included electrocardiogram QT prolongation, thrombocytopenia, and decreased hemoglobin. Abemaciclib was specifically linked to diarrhea, vomiting, and interstitial lung disease.
CONCLUSIONS: Our analysis revealed that palbociclib showed a higher risk of hematologic toxicity. Ribociclib showed higher risks of hepatotoxicity, nephrotoxicity, and QT prolongation. Abemaciclib showed higher risks of hepatotoxicity, gastrointestinal effects, interstitial lung disease, and thrombosis. These findings provide valuable insights for CDK4/6 inhibitor selection.

OBJECTIVE: Human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) is a new entity considered a biologically distinct subtype from HER2-zero BC. However, the importance of HER2 low expression on the activity of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) remains unclear.
METHODS: We conducted a single-center retrospective study including hormone receptor-positive (HR +) /HER2- metastatic BC (mBC) patients treated with CDK4/6i plus endocrine treatment (ET) as first-line therapy. Clinical outcomes were analyzed according to HER2 expression.
RESULTS: 258 women were analyzed with a median follow-up of 25.4 months; 39.9% had HER2 low, and 60.1% had HER2 zero BC. Median progression-free survival (mPFS) in the HER2-low group was 27.6 months compared with 44.3 months in the HER2-zero group (p = 0.341). In patients receiving ribociclib, the mPFS in the HER2-low group was 24.2 months compared with 53.1 months in the HER2-zero group (multivariate-adjusted HR: 1.981, 95 Cl 1.094-3.586; p = 0.024). The survival probabilities at 24, 36 and 48 months for the HER2 low and HER2 zero groups were 82%, 69%, 69% and 83%, 75% and 69%, respectively (p = 0.336). Objective response rate (p = 0.179) and disease control rate (p = 0.338) did not significantly differ between HER-2-low and HER-2-zero groups.
CONCLUSIONS: The mPFS in the Her2-zero group was almost twice that of the Her2-low group, but the difference was not statistically significant. mPFS was significantly longer in the HER2-zero group compared to the HER2-low group in patients receiving ribociclib. More prospective studies are needed to understand the actual consequences of this biomarker.

The most common toxicities associated with cyclin-dependent kinase (CDK) 4/6 inhibitor therapy include decreased leukopenia and neutropenia due to the inhibition of CDK6 of leukocyte and neutrophil precursors in bone marrow. These hematological toxicities are more commonly observed with palbociclib administration than with abemaciclib administration, which is approximately 13 times more selective against CDK4 than CDK6. Thus, even though both successfully inhibit CDK4/6, the side effects of palbociclib and abemaciclib differ due to differences in selectivity. Recent reports have suggested an association between palbociclib and medication-related osteonecrosis of the jaw; however, reports on this association are inconsistent. This study investigated the potential association of palbociclib and abemaciclib with MRONJ using the FAERS. Signals of \"Osteonecrosis of jaw\" were detected only in females using palbociclib (cROR025: 2.08). Other signals detected included stomatitis-related adverse events with abemaciclib and intraoral soft tissue damage and infection with palbociclib. As previous exploratory studies have reported MRONJ signals for bisphosphonates and denosumab, we calculated the aROR for palbociclib-induced osteonecrosis of the jaw using concomitant bisphosphonates and denosumab as covariates. A signal was detected even after adjusting for sex, age, and concomitant medications as covariates (aROR0025: 5.74). A proper understanding of the differences in CDK selectivity is necessary for the appropriate use of CDK4/6 inhibitors. To the best of our knowledge, this is the first report on CDK4/6 inhibitors and drug-related osteonecrosis of the jaw. We believe that these results will offer new insights into adverse events related to the use of CDK4/6 inhibitors, and may aid in the proper use of CDK4/6 inhibitors.

OBJECTIVE: Endocrine therapy (ET) in combination with CDK 4/6 inhibitors (CDK 4/6i) is the standard treatment modality for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (mBC). There is uncertainty about the prognostic and predictive value of HER2-low status and whether HER2-low BC is an individual biologic subtype. In this study, we aimed to investigate the prognostic effect of HER2 expression status on survival in mBC patients treated with first-line ET plus CDK 4/6i.
METHODS: This multicenter retrospective study included patients with HR + /HER2-negative mBC cancer who were treated with first-line CDK 4/6i in combination with ET from January 2016 to March 2023. Patients were divided into two groups (HER2-low and zero), and survival and safety analyses were performed.
RESULTS: A total of 201 patients were included in this study; of these, 73 (36.3%) had HER2-low disease and 128 (63.7%) had HER2-zero. There were 135 patients (67.2%) treated with ribociclib and 66 (32.8%) with palbociclib. Most of the patients (75.1%) received aromatase inhibitors as combination-endocrine therapy. Baseline characteristics were similar between the two groups. The median follow-up was 19.1 months (range: 2.5-78.4). The most common side effect was neutropenia (22.4%). The frequency of grade 3-4 toxicity was similar between the HER2-zero and low patients (32% vs 31.5%; p = 0.939). Visceral metastases were present in 44.8% of patients. Between the HER2-low and zero groups, median PFS (25.2 vs 22.6 months, p = 0.972) and OS (not reached vs 37.5 months, p = 0.707) showed no statistically significant differences.
CONCLUSIONS: The prognostic value of HER2-low status remains controversial. Our study showed no significant effect of HER2 low expression on survival in patients receiving CDK 4/6i plus ET.

OBJECTIVE: Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting.
METHODS: The randomized multicenter phase II PACE trial enrolled patients with hormone receptor-positive/HER2- MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P.
RESULTS: Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = .62). The median PFS on F + P + A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline ESR1 and PIK3CA alterations.
CONCLUSIONS: The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.

BACKGROUND: CDK4/6 inhibitors in combination with traditional endocrine therapy (ET) have become the recommended first-line therapy for HR-positive/HER2-negative metastatic breast cancer (MBC). The aim of this prospective study was to evaluate the relationship between HER2-low expression and clinical outcomes in HR-positive/HER2-negative MBC patients receiving ET with or without CDK4/6 inhibitors.
METHODS: Between April 2016 and November 2019, 233 women with HR-positive/HER2-negative MBC who received ET with or without CDK4/6 inhibitors were enrolled into the study. The primary endpoint was progression-free survival (PFS). Statistical analysis included descriptive statistics, Kaplan-Meier curves, and Cox proportional hazards models.
RESULTS: HER2-low and HER2-zero subgroups in the CDK4/6 inhibitor plus ET cohort showed no significant difference in the median PFS (10.9 vs. 8.0 months; hazard ratio: 0.92; 95% confidence interval [CI]: 0.64-1. 30; p = 0.65), while HER2-low subgroup showed a significantly shorter median PFS compared to the HER2-zero subgroup in the ET alone cohort (5.6 vs. 17.0 months; hazard ratio: 2.82; 95% CI: 1.34-5.93; p = 0.0044). Moreover, the objective response rate was significantly lower in the HER2-low subgroup than the HER2-zero subgroup in the ET alone cohort (10.5% vs. 40.0%, p = 0.047). Lastly, no significant difference was observed in the overall survival between the HER2-low and HER2-zero subgroups in both cohorts.
CONCLUSIONS: This study suggested that HER2-low expression may predict the efficacy of ET but not that of CDK4/6 inhibitor plus ET in HR-positive/HER2-negative MBC patients. The results of this study highlight the importance of integrating HER2 status in tailoring personalized treatment strategies for HR-positive MBC.

Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with poor outcomes. To investigate novel therapeutic strategies, we characterized three new metastatic prostate cancer patient derived-tumor xenograft (PDTX) models and developed 3D spheroids from each to investigate molecular targeted therapy combinations including CDK4/6 inhibitors (CDK4/6i) with AKT inhibitors (ATKi). Metastatic prostate cancer tissue was collected and three PDTX models were established and characterized using whole-exome sequencing. PDTX 3D spheroids were developed from these three PDTXs to show resistance patterns and test novel molecular-targeted therapies. CDK4/6i\'s were combined with AKTi\'s to assess synergistic antitumor response to prove our hypothesis that blockade of AKT overcomes drug resistance to CDK4/6i. This combination was evaluated in PDTX three-dimensional (3D) spheroids and in vivo experiments with responses measured by tumor volumes, PSA, and Ga-68 PSMA-11 PET-CT imaging. We demonstrated CDK4/6i\'s with AKTi\'s possess synergistic antitumor activity in three mCRPC PDTX models. These models have multiple unique pathogenic and deleterious genomic alterations with resistance to single-agent CDK4/6i\'s. Despite this, combination therapy with AKTi\'s was able to overcome resistance mechanisms. The IHC and Western blot analysis confirmed on target effects, whereas tumor volume, serum PSA ELISA, and radionuclide imaging demonstrated response to therapy with statistically significant SUV differences seen with Ga-68 PSMA-11 PET-CT. These preclinical data demonstrating antitumor synergy by overcoming single-agent CDK 4/6i as well as AKTi drug resistance provide the rational for a clinical trial combining a CDK4/6i with an AKTi in patients with mCRPC whose tumor expresses wild-type retinoblastoma 1.

BACKGROUND: The optimal treatment approach for hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) with aggressive characteristics remains controversial, with lack of randomized trials comparing cyclin-dependent kinase (CDK)4/6-inhibitors (CDK4/6i) + endocrine therapy (ET) with chemotherapy + ET.
METHODS: We conducted an open-label randomized phase II trial (NCT03227328) to investigate whether chemotherapy + ET is superior to CDK4/6i + ET for HR+/HER2-negative MBC with aggressive features. PAM50 intrinsic subtypes (IS), immunological features, and gene expression were assessed on baseline samples.
RESULTS: Among 49 randomized patients (median follow-up: 35.2 months), median progression-free survival (mPFS) with chemotherapy + ET (11.2 months, 95% confidence interval [CI]: 7.7-15.4) was numerically shorter than mPFS (19.9 months, 95% CI: 9.0-30.6) with CDK4/6i + ET (hazard ratio: 1.41, 95% CI: 0.75-2.64). Basal-like tumors under CDK4/6i + ET exhibited worse PFS (mPFS: 11.4 months, 95% CI: 3.00-not reached [NR]) and overall survival (OS; mOS: 18.8 months, 95% CI: 18.8-NR) compared to other subtypes (mPFS: 20.7 months, 95% CI: 9.00-33.4; mOS: NR, 95% CI: 24.4-NR). In the chemotherapy arm, luminal A tumors showed poorer PFS (mPFS: 5.1 months, 95% CI: 2.7-NR) than other IS (mPFS: 13.2 months, 95% CI: 10.6-28.1). Genes/pathways involved in BC cell survival and proliferation were associated with worse outcomes, as opposite to most immune-related genes/signatures, especially in the CDK4/6i arm. CD24 was the only gene significantly associated with worse PFS in both arms. Tertiary lymphoid structures and higher tumor-infiltrating lymphocytes also showed favorable survival trends in the CDK4/6i arm.
CONCLUSIONS: The KENDO trial, although closed prematurely, adds further evidence supporting CDK4/6i + ET use in aggressive HR+/HER2-negative MBC instead of chemotherapy. PAM50 IS, genomic, and immunological features are promising biomarkers to personalize therapeutic choices.

CDK6 is a critical protein involved in the regulation of the cell cycle, playing an important role in the progression from the G1 to S phase. In breast cancer, dysregulation of this protein is involved in tumour development and progression, particularly in hormone receptor-positive (HR+) breast cancers. The upregulation of CDK6 have been observed in a subset of breast cancers, leading to uncontrolled progression of the cell cycle and increased proliferation of cells. The purpose of this abstract is to provide an outline of CDK6\'s role. In breast cancer and the therapeutic strategies targeting CDK6 using specific selected inhibitors. To discover viable therapeutic candidates after competitive inhibition of CDK6 with a small molecular drug complex, high throughput screening and docking studies were used. Further, we carried the compounds based on ADMET properties and prediction of activity spectra for substances analysis. Finally, two different compounds were selected to carry out MD simulations. CDK6-IMPHY002642 and CDK6-IMPHY005260 are the two compounds that were identified. Overall, our results suggest that the CDK6-IMPHY002642 and CDK6-IMPHY005260 complex was relatively stable during the simulation. The compounds that have been found can also be further examined as potential therapeutic possibilities. The combined findings suggest that CDK6, together with their genetic changes, can be investigated in therapeutic interventions for precision oncology, leveraging early diagnostics and target-driven therapy.Communicated by Ramaswamy H. Sarma.

OBJECTIVE: This phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians\' choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC).
METHODS: The initial randomized study design was later amended into a single-arm study, and all subsequent patients received ribociclib and ET. The primary end point was locally assessed progression-free survival (PFS). Secondary end points included overall survival (OS), clinical benefit rate (CBR), safety, compliance, and quality of life (QoL).
RESULTS: A total of 43 patients received ribociclib + ET and 10 patients received ET only. Median PFS was 12.4 months [95% CI 8.7-24.4] for patients who received ribociclib + ET and 4.75 months [95% CI 1.0-10.3] for those who received ET only. Median OS was not reached for patients who received ribociclib + ET, and 28 (65.1%) patients experienced clinical benefit [95% CI 49.1-79.0]. For patients who received ribociclib + ET, grade 3-4 hematological adverse events (AEs) occurred in 25 (58.1%) patients, and grade 3-4 non-hematological AEs occurred in 17 (39.5%) patients. During the study, 15 patients died - 14 of whom due to tumor-related reasons, and one patient due to pneumonia, which was not treatment-related.
CONCLUSIONS: The results of the AMICA study show a promising efficacy and safety of maintenance treatment with ribociclib added to ET after at least stable disease following the first metastatic chemotherapy in patients with HR+/HER2-mBC.
BACKGROUND: Anti-hormonal Therapy With Ribociclib in HR-positive/HER2- Negative Metastatic Breast Cancer (AMICA), NCT03555877, https://clinicaltrials.gov/ct2/show/NCT03555877.