Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.

Breast cancer is a heterogeneous disease consisting of different biological subtypes, with differences in terms of incidence, response to diverse treatments, risk of disease progression, and sites of metastases. In the last years, several molecular targets have emerged and new drugs, targeting PI3K/Akt/mTOR and cyclinD/CDK/pRb pathways and tumor microenvironment have been integrated into clinical practice. However, it is clear now that breast cancer is able to develop resistance to these drugs and the identification of the underlying molecular mechanisms is paramount to drive further drug development. Autophagy is a highly conserved homeostatic process that can be activated in response to antineoplastic agents as a cytoprotective mechanism. Inhibition of autophagy could enhance tumor cell death by diverse anti-cancer therapies, representing an attractive approach to control mechanisms of drug resistance. In this manuscript, we present a review of autophagy focusing on its interplay with targeted drugs used for breast cancer treatment.

Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors characterized by aggressive behavior, high risk of distant recurrence, and poor survival. Chemotherapy is still the main therapeutic approach for this subgroup of patients, therefore, progress in the treatment of TNBC remains an important challenge. Data derived from molecular technologies have identified TNBCs with different gene expression and mutation profiles that may help developing targeted therapies. So far, however, only a few of these have shown to improve the prognosis and outcomes of TNBC patients. Robust predictive biomarkers to accelerate clinical progress are needed. Herein, we review prognostic and predictive biomarkers in TNBC, discuss the current evidence supporting their use, and look at the future of this research field.

The introduction of CDK4/6 inhibitors in combination with endocrine therapy (ET) represents the most relevant advance in the management of hormone receptor (HR) positive, HER2-negative metastatic breast cancer over the last few years. This meta-analysis of randomized controlled trials (RCTs) is aimed to better characterize the efficacy of CDK4/6 inhibitors in some relevant subgroups and to test heterogeneity between different compounds with a particular focus on their ability to improve overall survival (OS). Pooled estimates of hazard ratios (HRs) were computed for progression-free survival (PFS), OS, and objective response rate (ORR) analysis in predefined subgroups to better understand treatment effect concerning specific patients’ characteristics. To estimate the absolute benefit in terms of PFS, pooled survival curves were generated by pooling the data of all trials. A total of eight RCTs were included. Adding a CDK4/6 inhibitor to ET is beneficial in terms of PFS, irrespective of the presence or not of visceral metastases, the number of metastatic sites, and the length of the treatment-free interval (TFI). The addition of CDK4/6 inhibitors produces a significant OS improvement, both in aromatase inhibitor (AI)-sensitive (HR 0.75, 95% CI) and AI-resistant patients (HR 0.77, 95% CI [0.67–0.89]). Pooled data from each single drug show that palbociclib remains the only class member not showing a statistically significant HR for OS (HR 0.83, 95% CI [0.68–1.02]).