UNASSIGNED: Since the European approval of CDK4/6 inhibitors in 2016, the treatment of patients with hormone-receptor-positive, HER2-negative metastatic breast cancer has changed significantly. Compared with chemotherapy, endocrine-based therapy has different treatment regimens and is associated with new side effects. Oral therapy aims for optimal drug efficacy and long treatment times while maintaining maximum independence and quality of life resulting in the conservation of medical staff resources.
UNASSIGNED: A monocentric analysis of therapy preferences of practitioners (25 nurses and physicians) and patients (11 on endocrine monotherapy, 17 on endocrine-based therapy, and 14 on intravenous chemotherapy) was performed using specific questionnaires. Preferences were assessed using a four-point Likert scale or bidirectional response options.
UNASSIGNED: All patients were highly supportive of oral therapy (mean agreement score on the Likert scale 1.3, p < 0.001 vs. all other options) and a consultation interval of 4 weeks (2.0, p = 0.015 vs. 3 weeks). Practitioners also preferred oral therapy (1.4) and visits every 4 weeks (1.6). In general, patients on oral therapies reported higher compatibility of their therapy with daily life than patients on chemotherapy (1.6 and 1.7 vs. 2.6, p = 0.006). Outpatient oncology is the main source of information for all patients, mainly in case of side effects (2.0) and open questions (1.8). Regarding oral antitumor therapy regimens, patients do not show a significant preference for a specific regimen, while practitioners prefer a continuous regimen (1.6) over a 21/7 regimen (21 days on and 7 days off therapy, 2.5). Patients are likely to accept mild side effects (e.g., neutropenia, diarrhea, polyneuropathy, fatigue) and would still adhere to their initial choice of regimen (continuous or 21/7). Only when side effects occur with a severity of CTCAE grade 3 do patients prefer the regimen in which the side effects occur for a shorter period of time.
UNASSIGNED: Patients and practitioners prefer oral antitumor therapy-both continuous and 21/7 regimens-over other application forms. Patient education and proper therapy management, supported by additional tools, contribute to the specific management of side effects and high adherence. This allows quality of life to be maintained during long-term therapy with CDK4/6 inhibitors in patients with metastatic breast cancer.

OBJECTIVE: To compare CDK4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) in the first- versus second-line setting for treatment of hormone receptor positive (HR+), HER2 negative, metastatic breast cancer (MBC) using real-world evidence.
METHODS: Patients with HR+, HER2 negative MBC, diagnosed between 2/3/2015 and 11/2/2021 and having ≥ 3 months follow-up were identified from the nationwide electronic health record-derived Flatiron Health de-identified database. Treatment cohorts included: (1) first-line ET with a CDK 4/6i (1st-line CDK4/6i) versus (2) first-line ET alone followed by second-line ET with a CDK4/6i (2nd-line CDK4/6i). Differences in baseline characteristics were tested using chi-square tests and two-sample t-tests. Time to third-line therapy, time to start of chemotherapy, and overall survival were compared using Kaplan-Maier method.
RESULTS: The analysis included 2771 patients (2170 1st-line CDK4/6i and 601 2nd-line CDK4/6i). Patients receiving 1st-line CDK4/6i were younger (75% vs 68% < 75 years old, p = 0.0001), less likely uninsured or not having insurance status documented (10% vs. 13%, p = 0.04), of better performance status (50% vs 43% with ECOG 0, p = 0.03), and more likely to have de novo MBC (36% vs. 24%, p < 0.001). Time to third-line therapy (49 vs 22 months, p < 0.001) and time to chemotherapy (68 vs 41 months, p < 0.001) were longer in those receiving first-line CDK4/6i. Overall survival (54 vs 49 months, p = 0.33) was similar between groups.
CONCLUSIONS: Use of CDK4/6i with first-, vs second-, line ET was associated with longer time to receipt of 3rd-line therapy and longer time to receipt of chemotherapy.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC.
METHODS: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan-Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135.
RESULTS: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48-1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41-0.66, p < 0.0001). The PALOMA-3 study analysed 520 patients with MBC. Within the 153 HER2-0 patients, the palbociclib-fulvestrant group showed a significantly longer PFS than the placebo-fulvestrant group (hazard ratio = 0.54, 95% CI 0.30-0.95, p = 0.034). Among the 367 HER2-low-positive patients, palbociclib-fulvestrant improved PFS (hazard ratio = 0.39, 95% CI 0.28-0.54, p < 0.0001).
CONCLUSIONS: The combination of a CDK4/6 inhibitor with ET significantly improved PFS in HER2-low-positive patients, while for HER2-0 patients, benefits were primarily observed in patients who had progressed on previous ET. Furthermore, HER2-0 patients may derive limited benefits from first-line CDK4/6 inhibitor treatment. Further work is needed to validate these findings and to delineate patient subsets that are most likely to benefit from the combination of CDK4/6 inhibitors and ET as first-line treatments.
BACKGROUND: None.

Aim: Assess factors associated with first-line (1L) treatment for HR+/HER2- metastatic breast cancer. Materials & methods: A cross-sectional survey of 250 US oncologists was conducted. Correlations were calculated between treatment class and demographics, treatment perceptions and other clinical/nonclinical characteristics. Results: Efficacy and safety/tolerability were critical in oncologists\' 1L decision-making. CDK4/6i use positively correlated with proportion of Medicare and postmenopausal patients (r = 0.54-0.67). Chemotherapy use demonstrated positive correlations with perimenopausal and premenopausal patients and symptom burden (r = 0.31-0.42). Aromatase inhibitor (AI) monotherapy correlated positively with anticipated treatment compliance (r = 0.42). Conclusion: Efficacy and safety/tolerability were most important to 1L decision-making. Clinical characteristics corresponded with CDK4/6i and chemotherapy use. Anticipated compliance was associated with AI monotherapy use.
Patients in the USA with a certain type of metastatic breast cancer (mBC, i.e., HR+/HER2−) might get chemotherapy or hormone therapy alone instead of new and potentially better medicines called cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) as their first treatment.Researchers wanted to understand how US cancer specialists decided the first treatment for this type of mBC. In a survey of 250 cancer specialists, researchers looked at different factors that might influence decision-making, including patient characteristics, doctors’ opinions about the treatments and other medical and non-medical features. This study also examined the connections between these factors and the cancer specialists’ choice of first treatment.Researchers found that cancer specialists care most about how well a treatment works and how safe it is when choosing the first treatment for HR+/HER2− mBC. They are more likely to use CDK4/6i if their patients have Medicare coverage or are older (i.e., women who have been through menopause). Chemotherapy is chosen if their patients are younger (i.e., women who are near and before menopause) or have more symptoms. Cancer specialists tend to choose first treatment with hormone therapy alone if they think their patients have a hard time following their treatment plan. The results showed that patient characteristics, doctors’ opinions of treatments and other medical and non-medical factors play a role in choosing treatment for HR+/HER2− mBC. By understanding these factors, researchers can work toward improving treatment choices for patients with this type of mBC.

Approximately 70% of newly diagnosed breast cancers are of the HR+/HER2- subtype. For the treatment of patients with HR+/HER2- metastatic breast cancer, current guidelines recommend the use of a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) in combination with endocrine therapy. In this review we assess existing literature concerning real-world effectiveness of palbociclib. Survival outcomes in terms of progression-free survival and overall survival are discussed and compared among the included real-world studies and in relation to the phase III PALOMA trials.
About 70% of newly diagnosed breast cancers belong to a specific subgroup called hormone receptor positive (HR+)/Human epidermal growth factor receptor 2 negative (HER2-). In cases with metastatic disease, doctors recommend a treatment approach combining drugs such as palbociclib along with hormonal therapy. Our review evaluates how palbociclib performs in patients in real-world practice situations, beyond clinical trial settings. We looked at two key measures: how long the cancer stays controlled (progression-free survival) and overall survival. The results from these real-world studies are discussed and compared to findings in clinical trials.

Relapsed or refractory diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) patients still faced with poor survival, representing an unmet clinical need. In-depth research into the disease\'s pathogenesis and the development of targeted treatment strategies are urgently needed. Here, we conducted a comprehensive bioinformatic analysis of gene mutation and expression using data from our center and public databases. Cell cycle-related genes especially for CDKN2A/B-CDK4/6/CCND1 machinery altered frequently in DLBCL and MCL. Clinically, high CDK4 and CDK6 expression were correlated with poor prognosis of DLBCL and MCL patients. Furthermore, we also validated the pharmacological efficacy of CDK4/6 inhibitor palbociclib and its synergy effect with PI3K inhibitor idelalisib utilizing in vitro cell lines and in vivo cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. Our results provided sufficient pre-clinical evidence to support the potential combination of palbociclib and idelalisib for DLBCL and MCL patients.

BACKGROUND: Mucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification.
METHODS: The anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
RESULTS: Dalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494-0.957) and 51.6% (95% CI, 0.307-0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue.
CONCLUSIONS: Dalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration.
BACKGROUND: ChiCTR2000031608.

Breast cancer is the second most common cancer amongst women in the United States following non-melanoma skin cancer. There were an estimated 276,480 new cases and 42,170 deaths in 2020. The lifetime risk for developing breast cancer in females is about 13%. In the United States this year approximately 284,200 people out of which 281,550 women and 2,650 men, will be diagnosed with invasive breast cancer. In recent years, treatment options with novel mechanisms have emerged. Cyclin dependent kinase (CDK) 4/6 inhibitors, namely palbociclib, ribociclib and abemaciclib, are relatively new targeted therapies for treating breast cancers express estrogen receptors (ER) and/or progesterone receptors (PR). CDKs are important regulatory enzymes in cell cycle transitions and cell division. Selective inhibition of CDK4/6 causes cell cycle to arrest in the G1 phase, resulting in reduced cell viability and tumor response. Abemaciclib is the only one approved as monotherapy. Palbociclib and ribociclib must be used as adjunctive therapy to endocrine therapy such as tamoxifen, aromatase inhibitors or fulvestrant. Common side effects include neutropenia, thrombocytopenia, fatigue, nausea, and vomiting. A black box warning for all CDK inhibitors is a rare but possibly fatal severe inflammation of the lungs, called pneumonitis. We present a fatal case of severe pneumonitis with superimposed fungal respiratory infection in the setting of hypogammaglobulinemia in a 65-year-old female with metastatic ER and PR positive, human epidermal growth factor receptor 2 (HER-2) negative breast cancer who received abemaciclib.

UNASSIGNED: For patients with hormone receptor-positive HER2-negeative metastatic breast cancer (HR+HER2- MBC), switching to another cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) or targeted drugs with different mechanism are considerable treatment strategies post-CDK4/6i. However, no clinical data has been reported on which of the two strategies is more effective. In order to explore optimal treatment option post-CDK4/6i, we performed a retrospective comparative cohort study to evaluate the efficacy and safety of abemaciclib-based therapy versus tucidinostat-based therapy after progression on palbociclib.
UNASSIGNED: We identified patients with HR+HER2- MBC who had received abemaciclib-based therapy or tucidinostat-based therapy after progression on palbociclib from the database of Chinese Society of Clinical Oncology Breast Cancer (CSCO BC). Baseline characteristics, efficacy and safety information of treatments were derived from seven research centers\' medical records. The primary endpoint was progression-free survival (PFS), the secondary endpoints were clinical benefit rate (CBR), PFS according to PIK3CA gene type, and safety.
UNASSIGNED: Between April 1st 2020 and June 30th 2022, a total of 149 patients were included, of whom 73 patients received abemaciclib plus endocrine therapy (ET), and 76 patients received tucidinostat plus ET. The majority of patients had visceral disease (124/149, 83.2%) and ≥3 metastatic organs (76/149, 51.0%), one third (48/149, 32.2%) had previously been treated ≥3 lines of ET at baseline in MBC setting. CBR was 38.4% (28/73) in abemaciclib group and 17.1% (13/76) in tucidinostat group (P=0.004). There was significant difference in PFS between abemaciclib group and tucidinostat group in both the whole population (5.0 vs. 2.0 months; hazard ratio =0.44; 95% CI: 0.31-0.64; P<0.001) and propensity score matched population. PIK3CA mutations occurred in 44.20% of patients who had undergone multigene sequencing. PIK3CA-mutant showed a negative effect on PFS of abemaciclib-based therapy. Neutropenia was the most common adverse event in both groups for any grade and grades 3-4. Common non-hematological toxicity occurred in abemaciclib group was diarrhea (27.4%), and were increased aspartate aminotransferase (AST) (26.3%), nausea (25.0%), vomiting (11.8%) and hypokalemia (13.2%) in tucidinostat group.
UNASSIGNED: Our study suggests superiority of abemaciclib-based therapy over tucidinostat-based therapy in patients progressed on palbociclib, which merits further assessment in larger and prospective trials.

Anti-CDK4/6 therapy has been employed for the treatment for head and neck squamous cell carcinoma (HNSCC) with CDK4/6 hyperactivation, but the response rate is relatively low. In this study, we first showed that CDK4 and CDK6 was over-expressed and conferred poor prognosis in HNSCC. Moreover, in RB-positive HNSCC, STAT3 signaling was activated induced by CDK4/6 inhibition and STAT3 promotes RB deficiency by upregulation of MYC. Thirdly, the combination of Stattic and CDK4/6 inhibitor results in striking anti-tumor effect in vitro and in Cal27 derived animal models. Additionally, phospho-STAT3 level negatively correlates with RB expression and predicts poor prognosis in patients with HNSCC. Taken together, our findings suggest an unrecognized function of STAT3 confers to CDK4/6 inhibitors resistance and presenting a promising combination strategy for patients with HNSCC.