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Objective: We aimed to evaluate the use of CDK4/6 inhibitors as a risk factor for medication-related osteonecrosis of the jaw (MRONJ) in a cohort of patients with metastatic breast cancer treated with denosumab., Methods: This was a multicentre, retrospective, observational study. All patients with breast cancer treated with denosumab (January 2011-December 2022) were included. The relationship between CDK4/6 inhibitors and MRONJ was analysed., Results: A total of 243 patients were included, ninety-five (44.2%) of whom used a CDK4/6 inhibitor. There were 21 patients with MRONJ. In patients treated with denosumab without CDK4/6 inhibitors, the incidence of MRONJ and mean time to the occurrence of MRONJ were 6.6% (8/120) and 16.8 months (SD 7.8), respectively; in patients treated with denosumab and CDK4/6 inhibitor, these values were 13.7% (13/95) and 15.4 months (SD 8.7), respectively. The difference in the incidence was not significant ( p = 0.085). Among the 19 patients who used abemaciclib, the probability of MRONJ occurrence was significantly higher compared to patients not using CDK4/6 inhibitors ( p = 0.0178)., Conclusions: These results suggest that the incidence of MRONJ in patients with metastatic breast cancer treated with denosumab is higher, and the onset of MRONJ occurs earlier in the presence of CDK4/6 inhibitors. The differences were statistically significant in the patients who used abemaciclib. Given that the use of this combination is very common in routine clinical practice, it would be advisable to carry out larger prospective studies to clarify the risk of this association.

Since therapy-induced senescence (TIS) can either support or inhibit cancer progression, identifying which types of chemotherapeutic agents can produce the strongest anti-tumor TIS is an important issue. Here, cyclin-dependent kinase4/6 inhibitors (CDK4/6i)-induced senescence was compared to the TIS induced by conventional DNA-damaging agents. Despite both types of agents eliciting a similar degree of senescence, we observed increased expression of the senescence-associated secretory phenotype (SASP) and ligands related to pro-tumor immunity (IL6, CXCL8, TGFβ, CD274, and CEACAM1) and angiogenesis (VEGFA) mainly in TIS induced by DNA-damaging agents rather than by CDK4/6i. Additionally, although all agents increased the expression of anti-tumor immunomodulatory proteins related to antigen presentation (MHC-I, B2M) and T cell chemokines (CXCL9, 10, 11), CDK4/6i-induced senescent cells still maintained this expression at a similar or even higher intensity than cells treated with DNA-damaging agents, despite the absence of nuclear factor-kappa-B (NF-κB) and p53 activation. These data suggest that in contrast with DNA-damaging agents, which augment the pro-tumorigenic microenvironment via pro-inflammatory SASP, CDK4/6i can generate TIS only with antitumor immunomodulatory proteins., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: To estimate the cost-effectiveness of adding a CDK4/6 inhibitor to standard endocrine therapy in the first-line setting for advanced HR+/HER2- breast cancer in postmenopausal and premenopausal women, from the perspective of the Mexican public healthcare system., Methods: We used a partitioned survival model to simulate relevant health outcomes in a synthetic cohort of patients with breast cancer derived from the PALOMA-2, MONALEESA-2, MONARCH-3 trials for postmenopausal patients, and from the MONALEESA-7 study for premenopausal patients. Effectiveness was measured in life years gained. Cost-effectiveness is reported through incremental cost-effectiveness ratios (ICER)., Results: In postmenopausal patients, palbociclib led to an increase of 1.51 life years, ribociclib of 1.58 years, and abemaciclib of 1.75 years, compared to letrozole alone. The ICER was 36,648 USD, 32,422 USD, and 26,888 USD, respectively. In premenopausal patients, ribociclib led to an increase of 1.82 life years when added to goserelin and endocrine therapy, with an ICER of 44,579 USD. In the cost minimization analysis, for postmenopausal patients, ribociclib was the treatment with the highest costs due to follow-up requirements., Conclusion: Palbociclib, ribociclib, and abemaciclib demonstrated a significant increase in effectiveness in postmenopausal patients, and ribociclib in premenopausal patients, when added to standard endocrine therapy for patients with advanced HR+/HER2- breast cancer. At the national stablished willingness to pay, only the addition of abemaciclib to standard endocrine therapy in postmenopausal women would be considered cost-effective. However, differences on results between therapies for postmenopausal patients were not statistically significant., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Aim: To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa. Methods: This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A. Results: In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346–0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm (p < 0.0001, measurable disease population). In cohort B, 104 patients were randomly assigned to the abemaciclib arm and 53 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: 11.5 versus 5.6 months; hazard ratio 0.376; 95% CI 0.240–0.588; p < 0.0001). ORR was 50.0% in the abemaciclib arm and 10.5% in the placebo arm (p < 0.0001, measurable disease population). The most frequent grade ⩾3 adverse events in the abemaciclib arms were neutropenia, leukopenia, and anemia (both cohorts), and lymphocytopenia (cohort B). Conclusion: The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population. Trial Registration: ClinicalTrials.gov identifier: NCT02763566. [ABSTRACT FROM AUTHOR]

Insulinoma-associated protein 1 (INSM1), a zinc finger transcriptional factor, is proven to be deregulated in several types of cancers. However, comprehension of the molecular mechanism of INSM1-mediated tumor progression remains poor. Here, we show that the radioresistant nasopharyngeal carcinoma (NPC) patients have higher expressions of INSM1 that correlated with poor prognosis. Genetic manipulation of INSM1 expression sufficiently controls the response of NPC cells to irradiation (IR). Mechanistically, cells exposed to IR, increased intracellular INSM1 competitively disrupts the interaction of cyclin D1 and CDK4 resulting in cell survival by the cyclin D1-dependent DNA repair machinery. Moreover, knockdown of INSM1 sensitives NPC cells to IR in vivo and protects xenograft mice from mortality. Taken together, these results indicate that INSM1 modulates NPC to radiotherapy by controlling cyclin D1-dependent DNA repair machinery that could be manipulated as a novel molecular target for NPC therapy. [ABSTRACT FROM AUTHOR]

The goal of this project was to evaluate the association of candidate genetic variant rs2069502 of the CDK4 gene with breast cancer and the effect of variant genotypes on the serum concentration of CDK4 enzyme and consequently, on the occurrence of breast cancer and breast cancer subtypes in the studied population. A total of 80 breast cancer patients were divided into 4 subtypes, Luminal A, Luminal B, Her2/neu enriched and TPN, while 80 healthy individuals were enrolled as controls. Our results revealed that there were no significant differences between breast cancer patients and control groups and among breast cancer subtypes in the serum concentration of CDK4 (p-value >0.05). An allelic and genotypic association of rs2069502 with breast cancer showed that there were no significant allele frequency differences, in both alleles A and G, between breast cancer patients and the control group(p-value > 0.05). Association of rs2069502 genotypes with breast cancer and under different inheritance models revealed that there was no significant association between rs2069502 genotypes and breast cancer (p-value> 0.05). The association of rs2069502 genotypes with CDK4 serum concentration showed the presence of a significant difference between A/A and A/G, A/A and G/G in the CDK4 level (p-value < 0.05). But A/G and G/G did not show any significant difference in the CDK4 level. The rs2069502 CDK4 gene did not show any significant association with breast cancer except, in the genotyping frequency among breast cancer subtypes. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LSCC) exhibits a number of similarities with lung adenocarcinoma (LA) in terms of copy number alterations. However, compared with LA, the range of genetic alterations in LSCC is less understood. In the present study, a large-scale literature-based search of LA-associated genes and LSCC-associated genes was performed to identify the genetic basis in common with these two diseases. For each of the LA-associated genes, a mega-analysis was performed to test its expression variations in LSCC using 11 RNA expression datasets, with significant genes identified using statistical analysis. Subsequently, a functional pathway analysis was performed to identify a possible association between any of the significant genes identified from the mega-analysis and LSCC, followed by a co-expression analysis. A multiple linear regression (MLR) model was employed to investigate the possible influence of sample size, country of origin and study date on gene expression in patients with LSCC. Disease-gene association data analysis identified 1,178 genes involved in LA, 334 in LSCC, with a significant overlap of 187 genes (P<1.02×−161). Mega-analysis revealed that three LA-associated genes, such as solute carrier family 2 member 1 (SLC2A1), endothelial PAS domain protein 1 (EPAS1) and cyclin-dependent kinase 4 (CDK4), were significantly associated with LSCC (P<1.60×10−8), with multiple potential pathways identified by functional pathway analysis, which were further validated by co-expression analysis. The present MLR analysis suggested that the country of origin was a significant factor for the levels of expression of all three genes in patients with LSCC (P<4.0×10−3). Collectively, the present results suggested that genes associated with LA should be further investigated for their association with LSCC. In addition, SLC2A1, EPAS1 and CDK4 may be novel risk genes associated with LA and LSCC. [ABSTRACT FROM AUTHOR]

Abstract Cyclin D‐CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER‐positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors. We had shown that the activating T172 phosphorylation of CDK4 is the central rate‐limiting event that initiates the cell cycle decision and signals the presence of active CDK4. Here, we report that the profile of post‐translational modification including T172 phosphorylation of CDK4 differs among breast tumors and associates with their subtypes and risk. A gene expression signature faithfully predicted CDK4 modification profiles in tumors and cell lines. Moreover, in breast cancer cell lines, the CDK4 T172 phosphorylation best correlated with sensitivity to PD0332991. This gene expression signature identifies tumors that are unlikely to respond to CDK4/6 inhibitors and could help to select a subset of patients with HER2‐positive and basal‐like tumors for clinical studies on this class of drugs.

The Draize test has been used on rabbits since the 1960s to evaluate the irritation caused by commercial chemicals in products such as cosmetics or hairdressing products. However, since 2003, such tests, including the Draize test for cosmetics, have been prohibited in European countries because they are considered problematic to animal welfare. For this reason, replacement of in vivo methods with the alternative in vitro methods has become an important goal. In this study, we established a corneal epithelial cell line co-expressing a mutant cyclin-dependent kinase 4 (CDK4), Cyclin D1, and telomerase reverse transcriptase (TERT). The established cell line maintained its original morphology and had an enhanced proliferation rate. Furthermore, the cells showed a significant, dose-dependent decrease in viability in an irritation test using glycolic acid and Benzalkonium chloride. These cells can now be shared with toxicology scientists and should contribute to increasing the reproducibility of chemical testing in vitro.

Background: Studies have demonstrated the efficacy of Palbociclib (CDK 4/6 inhibitor), Gedatolisib (PI3K/mTOR dual inhibitor) and PD0325901 (MEK1/2 inhibitor) in colorectal cancer (CRC), however single agent therapeutics are often limited by the development of resistance., Methods: We compared the anti-proliferative effects of the combination of Gedatolisib and Palbociclib and Gedatolisib and PD0325901 in five CRC cell lines with varying mutational background and tested their combinations on total and phosphoprotein levels of signaling pathway proteins., Results: The combination of Palbociclib and Gedatolisib was superior to the combination of Palbociclib and PD0325901. The combination of Palbociclib and Gedatolisib had synergistic anti-proliferative effects in all cell lines tested [CI range: 0.11-0.69] and resulted in the suppression of S6rp (S240/244), without AKT reactivation. The combination of Palbociclib and Gedatolisib increased BAX and Bcl-2 levels in PIK3CA mutated cell lines. The combination of Palbociclib and Gedatolisib caused MAPK/ERK reactivation, as seen by an increase in expression of total EGFR, regardless of the mutational status of the cells., Conclusion: This study shows that the combination of Palbociclib and Gedatolisib has synergistic anti-proliferative effects in both wild-type and mutated CRC cell lines. Separately, the phosphorylation of S6rp may be a promising biomarker of responsiveness to this combination.

Pancreatic β-cell dysfunction is a key factor in the development of type 2 diabetes. Pancreatic β-cell senescence accelerates abnormal glucose metabolism, which decreases insulin secretion and cell regeneration ability, eventually leading to diabetes. A cholesterol oxidation product, 7-ketocholesterol (7-KC) can affect pancreatic β-cell function. However, its role in pancreatic β-cell senescence has not been reported. We investigated the role of 7-KC in pancreatic β-cell senescence and its underlying molecular mechanism in MIN6 cells. MIN6 cells were treated with 25 μmol/L 7-KC for 24 h and the proportion of senescent cells was detected based on senescence-associated β-galactosidase (SA-β-gal) activity. The cell cycle, DNA damage, and the senescence-associate secretory phenotype (SASP) and protein expression were detected by flow cytometry, immunofluorescence, and western blotting, respectively. 7-KC can significantly increase SA-β-gal activity, promoted G0/G1 arrest, DNA damage, and interleukin-1β expression in MIN6 cells and significantly inhibited insulin synthesis. Further studies indicated that 7-KC induced β-cell senescence by inhibiting the SIRT1/CDK4-Rb - E2F1 signaling pathway.

Treatment adherence is crucial for optimal outcomes in advanced breast cancer, but can be challenging due to various factors, i.e . patients' attitudes and behavior upon diagnosis, and complex therapies with high adverse effect rates. Our aim was to explore the adherence to oral anticancer medications (OAM) in women with advanced breast cancer, focusing on cyclin-dependent kinase 4 and 6 inhibitors (CDKI), and identify factors associated with the adherence. We conducted a cross-sectional study at the University Hospital Centre Zagreb, Croatia, involving women with stage IV advanced breast cancer receiving OAM. Data collection included a questionnaire assessing socio-demographic and clinical information, Beck Depression Inventory-II for depressive symptoms, Medication Adherence Report Scale (MARS-5) for adherence to OAM, and Beliefs about Medicines Questionnaire. Plasma concentrations of CDKI were confirmed by LC-MS/MS in three randomly selected participants. A total of 89 women were included. The most prescribed OAMs were anti-estrogen (71.3 %) and CDKI (60.9 %). MARS-5 scores (mean: 24.1 ± 1.6) correlated with CDKI plasma concentrations. Forgetfulness was the primary reason for non-adherence (25.9 %). Women receiving CDKI ( p = 0.018), without depressive symptomatology ( p = 0.043), and with more positive beliefs about medicines were more adherent ( p < 0.05). This study enhances understanding of medication adherence in advanced breast cancer and identifies influential factors., (© 2023 Matea Baković et al., published by Sciendo.)

Background: Although the roles of PD-L1 in promoting tumor escape from immunosurveillance have been extensively addressed, its non-immune effects on tumor cells remain unclear., Methods: The spatial heterogeneity of PD-L1 staining in human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) tissues was identified by immunohistochemistry. Three-dimensional (3D) specific cell-led invasion assay and 3D cancer spheroid model were used to investigate the roles of PD-L1 hi leader cells in collective invasion. The impact of M1 macrophages on specific PD-L1 expression in leader cells and its mechanisms were further studied. Finally, the effect of combination therapy of anti-PD-L1 and CDK4 inhibitor on HPV-positive tumors were evaluated on a mice model., Results: Here, we observed a distinctive marginal pattern of PD-L1 expression in HPV-positive HNSCC tissues. By mimicking this spatial pattern of PD-L1 expression in the 3D invasion assay, we found that PD-L1 hi cells led the tumor collective invasion. M1 macrophages induced specific PD-L1 expression in leader cells, and depletion of macrophages in tumor-bearing mice abrogated PD-L1 hi leader cells and collective invasion. Mechanistically, TNF-α secreted by M1 macrophages markedly increased the abundance of PD-L1 via CDK4/ubiquitin-specific peptidase 14-mediated deubiquitination of PD-L1. We also found that suppression of CDK4 enhanced the efficacy of anti-PD-L1 therapy in an E6/E7 murine model., Conclusions: Our study identified TNF-α/CDK4/ubiquitin-specific peptidase 14-mediated PD-L1 stability as a novel mechanism underlying M1 macrophage-induced PD-L1 hi leader cells and collective tumor invasion, and highlighted the potential of the combination therapy of anti-PD-L1 and CDK4 inhibitor for HPV-positive HNSCC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The treatment landscape of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer has evolved dramatically in recent years. While the combination of endocrine therapy and a cyclin-dependent kinase 4/6 inhibitor is accepted as standard first-line treatment in most settings without visceral crisis, newer therapies have challenged traditional treatment models where cytotoxic chemotherapy was previously felt to be the only second-line option at time of progression. The incorporation of next-generation sequencing has led to the identification of molecular targets for therapeutic agents, including phosphatidylinositol 3-kinase and ESR1, though similar pathways can be targeted even in the absence of a mutation, such as with use of inhibitors of mammalian target of rapamycin. Current data also supports the use of cyclin-dependent kinase inhibitors beyond progression, even prior to the patient's first introduction to chemotherapy. The abundance of therapeutic options not only delay time to cytotoxic chemotherapy and antibody-drug conjugate initiation, but has resulted in improvement in breast cancer survivorship. Many unanswered questions remain, however, as to the most efficacious way to sequence these novel agents. To assist in this decision-making, we will review the existing data on systemic therapy and propose a treatment paradigm., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cell division in eukaryotes is a highly regulated process that is critical to the life of a cell. Dysregulated cell proliferation, often driven by anomalies in cell Cyclin-dependent kinase (CDK) activation, is a key pathological mechanism in cancer. Recently, selective CDK4/6 inhibitors have shown clinical success, particularly in treating advanced-stage estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This review provides an in-depth analysis of the action mechanism and recent advancements in CDK4/6 inhibitors, categorizing them based on their structural characteristics and origins. Furthermore, it explores proteolysis targeting chimers (PROTACs) targeting CDK4/6. We hope that this review could be of benefit for further research on CDK4/6 inhibitors and PROTACs.

Biomarkers to identify metastatic breast cancer (mBC) patients resistant to CDK4/6 inhibition (CDK4/6i) are currently missing. We evaluated the usefulness of the monocyte-to-lymphocyte ratio (MLR), the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) as predictive markers for de novo resistance to CDK4/6i. Various blood cell counts and MLR, NLR, PLR were recorded before treatment initiation (baseline) and four weeks later from 97 mBC patients receiving endocrine therapy (ET) alone or in combination with CDK4/6i. Binary blood cell count/ratios (mean = cut-off) were related to outcome using Cox regression. High MLR (p = 0.001) and high NLR (p = 0.01) at baseline significantly correlated with a shorter progression-free survival (PFS) in the CDK4/6i cohort, independent of any other clinical parameter as determined by multivariate Cox regression. Both, high MLR (p = 0.008) and high NLR (p = 0.043) as well as a decrease in PLR after four weeks of CDK4/6i first line treatment (p = 0.01) indicated a shorter overall survival. Moreover, decreasing PLR (p = 0.043) and increasing mean corpuscular volume (MCV; p = 0.011) within the first cycle of CDK4/6i correlated with a shorter PFS and decreasing MLR (p = 0.039) within the first cycle of first-line CDK4/6i was also correlated with shorter PFS. In summary, easily assessable blood cell parameter were shown to have predictive, monitoring and prognostic value and thus, could, in future, be used for individualized CDK4/6i therapy management. Most importantly, the imbalance of NLR and MLR at baseline might serve as predictive marker for de novo resistance to CDK4/6i in mBC patients., (© 2023. The Author(s).)

We report a case of a breast cancer patient with bone marrow carcinomatosis and disseminated intravascular coagulation who was treated with chemotherapy and a CDK4/6 inhibitor. The patients, a 68-year-old woman, presented to our hospital with anorexia and was found to have multiple liver metastases of breast cancer. Furthermore, she had anemia and thrombocytopenia, and a bone marrow biopsy showed bone metastasis of the breast cancer. Therefore, a diagnosis of bone marrow carcinomatosis and disseminated intravascular coagulation was made. Treatment was started with chemotherapy(epirubicin and cyclophosphamide)and subsequently changed to an aromatase inhibitor(letrozole)and a CDK4/4 inhibitor(abemaciclib) and was maintained without exacerbation of the patient's condition.

Introduction: Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses., Materials and Methods: A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors., Results: We identified eight cases, most of them at stages 0-1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug's half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific., Conclusion: We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Breast cancer (BC) is a common malignancy in women, with hormone receptor (HR)-positive subtype responsible for approximately 70% of cases. Currently, patients with metastatic HR-positive BC rely on endocrine therapy and cyclin-dependent kinase (CDK)-4/6 inhibitors for treatment. Currently, approved CDK4/6 inhibitors include palbociclib, ribociclib, and abemaciclib. However, clinical evidence of CDK-4/6 inhibitor resistance is emerging, suggesting that the gap in the knowledge of its resistance mechanism requires further investigation. This review discusses the mechanisms of CDK4/6 inhibitor resistance in BC, including both intrinsic and extrinsic mechanisms. We also discuss possible alternative strategies to overcome CDK4/6 inhibitor resistance in future clinical applications., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The development of oral cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, including palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for patients with hormone-receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (BC). When combined with an aromatase inhibitor or fulvestrant, these agents have been approved as first-line therapy in the metastatic setting. Abemaciclib has also gained FDA approval for patients with HR-positive, HER2-negative, node-positive, early BC at high risk of recurrence. Moreover, ribociclib has recently improved disease-free survival in patients with stage II or III HR+/HER2-negative early BC. CDK4/6 inhibitors have favorable safety profiles. However, the available agents have different toxicity profiles that must be clearly discussed with the patients for optimal clinical decisions. This manuscript aims to review CDK4/6 inhibitor-related treatment-associated adverse events, identify risk factors for intolerable adverse events, and assess their safety in special patient populations such as the elderly and those with renal insufficiency. Enhanced knowledge and understanding of CDK4/6 inhibitor-related toxicities can improve treatment strategies and ultimately enhance patient care., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matteo Lambertini reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD and Exact Sciences and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Knight and Takeda, Travel Grants from Gilead and Daiichi Sankyo, and research support (to the Institution) from Gilead outside the submitted work. Cinzia Solinas received travel grants from Ipsen and Lilly outside the submitted work. Nerina Denaro report: support for attending meetings and/or travel from Merck, msd, Novartis, and pierre fabre. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bms, msd, and merck Ornella Gerrone report: consulting fees from EISAI, Daiichi-Sankyo, Astra Zeneca, Gilead, and Seagen. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, Novartis, Lilly and MSD. Support for attending meetings and/or travel from Novartis, Daiichi-Sankyo, and Ipsen. Mario Scartozzi reports: consulting fees from MERCK, MSD, SERVIER, AMGEN, and GILEAD. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MERCK, MSD, SERVIER, and EISAI. Support for attending meetings and/or travel from MERCK. Participation on a Data Safety Monitoring Board or Advisory Board for ROTTAPHARM BIOTECH. All other authors have no conflict of interest to declare related to the present topic., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6is) in combination with Endocrine Therapy (ET) represent the standard frontline therapy for patients with Hormone Receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic Breast Cancer (mBC). Clinical activity and efficacy of CDK4/6is-based therapies have been proven both in the endocrine sensitive and resistant settings. Therapy resistance eventually underpins clinical progression to any CDK4/6is-based therapies, yet there is a lack of validated molecular biomarkers predictive of either intrinsic or acquired resistance to CDK4/6is in clinical practice. As the "post-CDK4/6is" landscape for the management of HR-positive/HER2-negative mBC is rapidly evolving with the introduction of novel therapies, there is an urgent need for the definition of clinically relevant molecular biomarkers of intrinsic/acquired resistance mechanisms to CDK4/6is. This narrative review outlines the role of currently approved CDK4/6is-based therapies, describes the most relevant molecular biomarkers of CDK4/6is-resistance, and ultimately provides a perspective on the clinical and research scenario., Competing Interests: Declaration of Competing Interest GC received honoraria for speaker's engagement: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, MSD; Honoraria for providing consultancy: Roche, Seattle Genetics, NanoString; Honoraria for participating in Advisory Board: Roche, Lilly, Pfizer, Foundation Medicine, Samsung, Celltrion, Mylan; Honoraria for writing en-gagement: Novartis, BMS; Honoraria for participation in Ellipsis Scientific Affairs Group; Insti-tutional research funding for conducting phase I and II clinical trials: Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Sero-no, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, Medimmune. CC reports personal fees for consulting, advisory role and speakers’ bureau from Lilly, Roche, Novartis, MSD, Seagen, Gilead and Pfizer. All other authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: CDK4/6 inhibitors (ribociclib, palbociclib and abemaciclib) are 1st line therapy in metastatic breast cancer (MBC). No comparative data exists between agents regarding toxicity or efficacy., Methods: A retrospective study was performed at our tertiary referral centre evaluating patients on a CDK4/6 inhibitor for MBC between July 2017 and December 2021. Toxicity was evaluated along with variability in full blood counts and liver function over the first 12 weeks of therapy., Results: Two hundred and seventeen patients were treated (palbociclib 59%, abemaciclib 25% and ribociclib 16%). 86% received the agent as 1st line therapy. Most patients were white women with a median age of 61 years (32-95) and ECOG 0/1. Twelve patients were switched to an alternative CDK4/6 inhibitor due to toxicity and two did not tolerate this. Toxicity profiles of agents were consistent with published trials. However, there was greater overlap in hepatitis, diarrhoea and bone marrow suppression. Blood results indicated a minimum of four weeks treatment before development of neutropenia. Forty percent of patients went onto have subsequent lines of therapy. The progression-free survival per agent was palbociclib 27.9 months (95% CI 23-32.5), ribociclib 29 months (95% CI 21.5-37.0) and abemaciclib 20.6 months (95% CI 15.0-26.0). The overall survival was palbociclib 38.0 months (95% CI 33.5-42.5), ribociclib 33.9 months (95% CI 26.7-41.1) and abemaciclib 27.3 months (95% CI 22.5-32.1)., Conclusions: Toxicity across CDK4/6 inhibitors overlaps. The optimal sequence of therapies post CDK4/6 inhibitors remains unknown but rechallenge with an alternative agent is possible., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The adjuvant endocrine therapy (AET) of HR+ EBC has been changing in recent years. Aromatase inhibitors (AIs) as an upfront strategy (or as part of a switch strategy) have been added to the choice of Tamoxifen (T) alone. Increased TE risk is well known in T-treated patients, while AIs have shown a reduced TE rate. By adding the cyclin dependent kinase 4/6 inhibitors (CDK4/6) to AIs, an increase in TE rate has been shown. We conducted this meta-analysis to evaluate the impact of the AETs on TE incidence. Twelve randomized phase III trials were included. Four trials evaluated the upfront strategy, 6 assessed the switch and 2 the combination with a CDK4/6 inhibitor. The new AETs did not significantly modify or affect the rate of TE events (OR 0.847, 95% CI, 0.528-1.366, P = .489). The OR for CDK4/6 inhibitor plus ET vs. ET was 3.635 (P = .002). Excluding the CDK4/6 inhibitors, the overall OR for AIs vs. T was 0.628 (P < .001), while it was 0.781 (P = .151) for switching T vs. continuing T for 5 years, and 0.52 (P < .0001) for the upfront strategies with AIs. The AIs alone or plus CDK4/6 inhibitors did not affect the rate of TE events. AIs as an upfront strategy is the safest AET, associated with the lowest TE incidence. The switch strategy increases TE rate, whereas the addition of CDK4/6 to the standard AET was shown to significantly increase TE events. The results of the currently ongoing trials with CDK4/6 inhibitors will help obtain additional data to evaluate any differences among the different CDK4/6 inhibitors and clarify the weight of TE adverse events in the benefit/risk balance of this new adjuvant strategy., Competing Interests: Disclosure LM, AT have served as a member of an advisory board and received personal fees and travel grants from Pfizer and Eli Lilly. LC has served as consultant, member of an advisory board and received personal fees and travel grants from Pfizer CM and FP received personal fees and travel grants from Pfizer and Eli Lilly. EB and MB received travel grants from Eli Lilly. IS, RD, FC and MD did not declare competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor-positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated the preclinical pharmacology and efficacy of the next-generation oral SERD camizestrant (AZD9833) and assessed ER-co-targeting strategies by combining camizestrant with CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR-targeted therapy in models of progression on CDK4/6i and/or ET. Camizestrant demonstrated robust and selective ER degradation, modulated ER-regulated gene expression, and induced complete ER antagonism and significant antiproliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi., Significance: Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment., (©2023 The Authors; Published by the American Association for Cancer Research.)