Cyclin-dependent kinases (CDK) 4/6 inhibitors, namely abemaciclib, palbociclib, and ribociclib, interfere with cell cycle progression, induce cell senescence and might promote cancer cell disruption by a cytotoxic T cells-mediated effect. Phase III randomized clinical trials have proven that CDK4/6 inhibitors (CDK4/6i) in combination with several endocrine agents improve treatment efficacy over endocrine agents alone for hormone receptor positive (HR+) HER2 negative (HER2–) metastatic breast cancer (MBC). Based on such results, these combinations have been approved for clinical use. Preclinical studies in cell cultures and mouse models proved that CDK4/6i are active against a broad spectrum of solid tumors other than breast cancer, including liposarcoma, rhabdomyosarcoma, non-small cell lung cancer, glioblastoma multiforme, esophageal cancer, and melanoma. The role of CDK4/6i in monotherapy in several solid tumors is currently under evaluation in phase I, II, and III trials. Nowadays, abemaciclib is the only of the three inhibitors that has received approval as single agent therapy for pretreated HR+ HER2– MBC. Here we review biological, preclinical and clinical data on the role of CDK4/6 inhibitors as single agents in advanced solid tumors.

Different peripheral blood parameters have emerged as prognostic biomarkers in breast cancer (BC), but their predictive role in Human Epidermal growth factor Receptor 2 positive (HER2+) advanced BC (aBC) patients receiving dual anti-HER2 blockade remains unclear. We evaluated the impact of the Pan-Immune-Inflammatory Value (PIV), defined as the product of peripheral blood neutrophil, platelet, and monocyte counts divided by lymphocyte counts, on the prognosis of HER2+ aBC patients treated with first line trastuzumab-pertuzumab-based biochemotherapy. We also evaluated the association between the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and the monocyte to lymphocyte ratio (MLR) and clinical outcomes. Cox regression models were used to estimate the impact of these variables, as well as of other clinically relevant covariates, on patient survival. We included 57 HER2+ aBC patients treated with taxane-trastuzumab-pertuzumab in our Institution. High baseline MLR, PLR, and PIV were similarly predictive of worse PFS at univariate analysis, but only high PIV was associated with a trend toward worse PFS at multivariable analysis. Regarding OS, both high PIV and MLR were associated with significantly worse patient survival at univariate analysis, but only the PIV was statistically significantly associated with worse overall survival at multivariable analysis (HR 7.96; 95% CI: 2.18–29.09). Our study reveals the PIV as a new and potent predictor of OS in HER2+ aBC patients treated with first line trastuzumab-pertuzumab-containing biochemotherapy. Prospective studies are needed to validate this new prognostic parameter in HER2+ aBC.

Purpose Obesity and insulin resistance have been associated with poor prognosis in breast cancer (BC). The present prospective study aimed to investigate the impact of metabolic syndrome (MetS) and its components on early BC (eBC) patients' outcome. Methods MetS was defined by the presence of 3 to 5 of the following components: waist circumference > 88 cm, blood pressure ≥ 130/≥ 85 mmHg, serum levels of triglycerides ≥ 150 mg/dL, high density lipoprotein < 50 mg/dL and fasting glucose ≥ 110 mg/dL. Seven hundred and seventeen patients with data on ≥ 4 MetS components at BC diagnosis were enrolled. Study population was divided into two groups: patients with < 3 (non-MetS) vs. ≥ 3 components (MetS). Categorical variables were analyzed by Chi-square test and survival data by log-rank test and Cox proportional hazards regression model. Results Overall, 544 (75.9%) and 173 (24.1%) women were categorized as non-MetS and MetS, respectively. MetS patients were more likely to be older, postmenopausal, and insulin-resistant compared to non-MetS patients (p < 0.05). In multivariate analysis, MetS patients had a numerically higher risk of relapse [disease-free survival (DFS), hazard ratio (HR) 1.51, p = 0.07] and a significantly higher risk of death compared to non-MetS patients [overall survival (OS), HR 3.01, p < 0.0001; breast cancer-specific survival (BCSS), HR 3.16, p = 0.001]. Additionally, patients with 1 to 2 components of MetS had an increased risk of dying compared to patients with 0 components (OS, HR 4.90, p = 0.01; BCSS, HR 6.07, p = 0.02). Conclusions MetS correlated with poor outcome in eBC patients. Among patients without full criteria for MetS diagnosis, the presence of 1 or 2 components of the syndrome may predict for worse survival.

Background: The PI3K/AKT/mTORC1 axis is implicated in hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2− mBC) resistance to anti-estrogen treatments. Based on results of the BOLERO-2 trial, the mTORC1 inhibitor everolimus in combination with the steroidal aromatase inhibitor (AI) exemestane has become a standard treatment for patients with HR+ HER2− mBC resistant to prior non-steroidal AI therapy. In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2− mBC that progressed after/on previous AI treatment. Therefore, two different molecules targeting the PI3K/AKT/ mTORC1 axis, namely everolimus and alpelisib, are available for patients progressing on/after previous AI treatment, but it is unclear how to optimize their use in the clinical practice. Main body of the abstract: Here, we reviewed the available clinical evidence deriving from the BOLERO-2 and SOLAR-1 trials to compare efficacy and safety profiles of everolimus and alpelisib in advanced HR+ HER2− BC treatment. Adding either compound to standard endocrine therapy provided similar absolute and relative PFS advantage. In the SOLAR-1 trial, a 76% incidence of grade (G) 3 or 4 (G3/G4) adverse events was reported, while G3/G4 toxicities occurred in 42% of patients in the BOLERO-2 trial. While alpelisib was only effective in patients with PIK3CA-mutated neoplasms, retrospective analyses indicate that everolimus improves exemestane efficacy independently of PIK3CA mutational status. (Continued on next page)Conclusions: Based on the available efficacy and safety data, the "new" alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the "old" everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2− mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status. BackgroundEndocrine therapy (ET) is the mainstay of treatment for patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (mBC) [1]. However, tumors initially responding to ET, including the most recent ET-Cyclin-Dependent Kinase 4/6 (CDK4/6) inhibitor combinations, almost invariably develop resistance [2][3][4]. Hence, the identification of targeted therapies that are able to revert or delay endocrine resistance is a clinically relevant issue.Aberrant signaling through the phosphatidylinositol 3kinase/protein kinase B (AKT)/mechanistic target of rapamycin complex 1 (PI3K/AKT/mTORC1) cascade is clearly implicated in endocrine resistance, thus providing the rationale for combining inhibitors of this pathway with currently available ET [5][6][7]. Based on the results of the BOLERO-2 trial, the mTORC1 inh...

Background: The immune system (innate and adaptive) is influenced by vitamin D3, which affects gene expression and inflammatory pathways. An umbrella review was conducted to evaluate the power and accuracy of data connecting vitamin D3 to the outcomes of COVID-19 infection and to appraise the proof provided by published meta-analyses. Methods: MEDLINE, Embase, and the Cochrane Library were searched from database inception to 31 May 2022. Meta-analyses of prospective or retrospective observational studies and randomized trials were included. Evidence of association was graded according to the established criteria: strong, highly suggestive, suggestive, weak, or not significant. Results: From 74 publications, 27 meta-analyses described five associations between vitamin D3 levels and supplementation and COVID-19 outcomes. Low levels of vitamin D3 were significantly associated with severity (highly suggestive evidence; OR = 1.97 [95% CI, 1.55–2.51], p < 0.01; I2 = 77%, p < 0.01) and mortality risk due to COVID-19 disease (OR = 1.83 [95% CI, 1.55–2.16], p < 0.01; I2 = 50%, p < 0.01). Vitamin D3 supplementation, after a diagnosis of COVID-19 infection, was associated with significantly reduced infection severity (e.g., ICU admission) and mortality. Conclusions: This umbrella review of the available evidence suggests that insufficient vitamin D3 may increase COVID-19 infection risk, severity, and mortality, in addition to showing a highly suggestive association between vitamin D3 supplementation and reduced severity and mortality among infected patients.