The latest and newest discoveries for advanced and metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer are the three cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) in association with endocrine therapy (ET). However, even if this treatment revolutionized the world and continued to be the first-line treatment choice for these patients, it also has its limitations, caused by de novo or acquired drug resistance which leads to inevitable progression after some time. Thus, an understanding of the overview of the targeted therapy which represents the gold therapy for this subtype of cancer is essential. The full potential of CDK4/6i is yet to be known, with many trials ongoing to expand their utility to other breast cancer subtypes, such as early breast cancer, and even to other cancers. Our research establishes the important idea that resistance to combined therapy (CDK4/6i + ET) can be due to resistance to endocrine therapy, to treatment with CDK4/6i, or to both. Individuals’ responses to treatment are based mostly on genetic features and molecular markers, as well as the tumor’s hallmarks; therefore, a future perspective is represented by personalized treatment based on the development of new biomarkers, and strategies to overcome drug resistance to combinations of ET and CDK4/6 inhibitors. The aim of our study was to centralize the mechanisms of resistance, and we believe that our work will have utility for everyone in the medical field who wants to deepen their knowledge about ET + CDK4/6 inhibitors resistance.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer over the last decade. These inhibitors are currently established as first- and second-line systemic treatment choices for both endocrine-sensitive and -resistant breast cancer populations alongside endocrine therapy (ET) or monotherapy. Data on targeted therapy continue to mature, and the number of publications has been constantly rising. Although these drugs have been demonstrated to prolong overall survival (as well as progression-free survival (PFS) in breast cancer patients), changing the paradigm of all current knowledge, they also cause important adverse events (AEs). This review provides the latest summary and update on the safety profile of the three CDK4/6 inhibitors, as it appears from all major phase II and III randomized clinical trials regarding palbociclib, ribociclib, and abemaciclib, including the most relevant 15 clinical trials.

Background: Metastatic renal cell carcinoma (mRCC) is an aggressive cancer characterised by an increased recurrence rate and an inadequate response to treatment. This study aimed to investigate the importance of the neutrophil-to-lymphocyte ratio (NLR) as a prognostic marker for long-term survival in patients with mRCC. Methods: We retrospectively analysed data from 74 patients with mRCC treated at our medical centre with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). We evaluated the predictive value of NLR for overall survival (OS) in these patients. Results: The median OS was 5.1 months in the higher NLR group (≥3) and 13.3 months in the lower NLR group (<3) (p < 0.0001). There was no significant difference in the OS between the TKI and ICI therapies in the low NLR group (12.9 vs. 13.6 months, p = 0.411) or in the high NLR group (4.7 vs. 5.5 months, p = 0.32). Both univariate and multivariate analyses revealed that a higher NLR was an independent prognostic factor of long-term survival in patients with mRCC treated with first-line therapy. Conclusions: This retrospective study showed that adding NLR to other Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) variables might improve the prognostic and predictive power of these models.

The management of renal cell carcinoma (RCC) has been revolutionized over the past two decades with several practice-changing treatments. Treatment for RCC often requires a multimodal approach: Local treatment, such as surgery or ablation, is typically recommended for patients with localized tumors, while stage IV cancers often require both local and systemic therapy. The treatment of advanced RCC heavily relies on immunotherapy and targeted therapy, which are highly contingent upon histological subtypes. Despite years of research on biomarkers for RCC, the standard of care is to choose systemic therapy based on the risk profile according to the International Metastatic RCC Database Consortium and Memorial Sloan Kettering Cancer Centre models. However, many questions still need to be answered. Should we consider metastatic sites when deciding on treatment options for metastatic RCC? How do we choose between dual immunotherapy and combinations of immunotherapy and tyrosine kinase inhibitors? This review article aims to answer these unresolved questions surrounding the concept of personalized medicine.

Tumor-to-tumor metastasis (TTM) is a rare phenomenon documented in patients with multiple primary cancers. This condition is defined as a metastasis between two true primary tumors. The most frequently reported recipient tumor is renal cell carcinoma (RCC), and the lung carcinomas are the most common metastatic tumor donors. Therefore, this paper attempts to address the current gap in knowledge about this rare phenomenon. The first part of this review outlines the recently proposed models and mechanisms involved in the TTM process. The second part then summarizes and analyzes previous case reports in the literature. We also present our experience with the case of lung cancer that metastasized into RCC. Given the sporadic incidence of TTM, no specific management guidelines exist. Therefore, considering TTM in patients with multiple primary tumors is important as it could potentially modify the oncological management offered.

Background: Over the past few years, significant advancements have been achieved in the front-line treatment of metastatic renal cell carcinomas (mRCCs). However, most patients will eventually encounter disease progression during this front-line treatment and require further therapeutic options. While treatment choices for mRCCs patients are determined by established risk classification models, knowledge of prognostic factors in subsequent line therapy is essential in patient care. Methods: In this retrospective, single-center study, patients diagnosed with mRCCs who experienced progression after first-line therapy were enrolled. Fifteen factors were analyzed for their prognostic impact on survival using the Kaplan–Meier method and the Cox proportional hazards model. Results: Poor International Metastatic RCCs Database Consortium (IMDC) and Memorial Sloan-Kettering Cancer Center (MSKCC) risk scores, NLR value > 3, clinical benefit < 3 months from a therapeutic line, and the presence of sarcomatoid differentiation were found to be poor independent prognostic factors for shortened overall survival. Conclusions: This study provided new insights into the identification of potential prognostic parameters for late-line treatment in mRCCs. The results indicated that good IMDC and MSKCC prognostic scores are effective in second-line therapy. Moreover, patients with NLR < 3, no sarcomatoid differentiation, and clinical benefit > 3 months experienced significantly longer overall survival.