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.

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.

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.

Immune-checkpoint inhibitors (ICIs) are the most effective treatments nowadays. Nivolumab was the second ICI used for treating solid tumors with amazing results. Patients treated with Nivolumab may react differently to this treatment. Some people tolerate this treatment very well without experiencing any adverse reactions, whilst some may have mild symptoms and a part of them can present severe reactions. In our research, we sought to identify the answers to four questions: 1. what type of cancer has more severe hypersensitivity reactions to Nivolumab, 2. what is the time frame for developing these severe reactions to Nivolumab, 3. whether it is best to continue or stop the treatment after a severe hypersensitivity reaction to Nivolumab and 4. what severe hypersensitivity reactions are the most frequent reported along Nivolumab treatment. This review also highlights another problem with regard to the usage of concomitant and prior medications or other methods of treatment (e.g., radiation therapy), which can also lead to severe reactions. Treatment with Nivolumab is very well tolerated, but patients should also be warned of the possibility of severe hypersensitivity reactions for which they should urgently see a doctor for a personalized evaluation. There are some options for individuals with severe hypersensitivity reactions, for eg. switching the medication or applying a desensitization protocol.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and endocrine therapy are the gold standards for systemic therapy for patients with hormone-positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer. Following progression, no prospective randomized data exist to help guide second-line treatment. Moreover, there is a scarcity of data on rechallenge treatment strategies with another CDK4/6 inhibitor after prior limiting toxicity. We report a real-world experience of rechallenging with abemaciclib after the prior reaction of grade 4 liver toxicity to ribociclib, with high transaminases values of more than 27 times the upper limit of normal (ULN) and unexpected grade 3 neutropenia and diarrhea after a few months of abemaciclib. After two years of treatment, the patient had stable oncological disease, with normal complete blood count, hepatic enzymes, and a very good performance status. We believe that our clinical case, along with others gathered from all around the world, will help with the consolidation of an unmet clinical need to readjust the treatment after experiencing toxicity to CDK4/6 inhibitors.

The neutrophil-to-lymphocyte ratio (NLR) at baseline treatment is an important marker of systemic inflammation, which is correlated with survival benefits in lung, breast, ovarian, bladder, and colorectal cancer. Programmed death-ligand 1 (PD-L1) expression is a biomarker with discording results regarding survival benefits in lung cancer. In our research, we studied the relationship between these two markers in patients with lung cancer. Patients with stage I, II, III, and IV lung cancer (n = 80) were included in this retrospective study. The NLR baseline was recorded before the initiation of treatment. The NLR cut-off value was 4. PD-L1 expression was determined by immunohistochemical staining. Univariate and multivariate survival analyses were conducted to test their prognostic value. NLR proved to be a significant prognostic factor for progression-free survival (PFS) (p=0.002, Log Rank) with a mean PFS of 27.7 months for low NLR patients and 12.8 months for high NLR patients. It was also significant for overall survival (OS) (p=0.007, Log Rank) with a mean OS of 52 months for low NLR patients and 41.6 months for high NLR patients. The prognostic impact of PD-L1 expression on PFS and OS was not statistically significant with a mean PFS of 23.1 months for PD-L1-negative patients and 15.8 months for PD-L1-positive patients (p=0.422, Log Rank). Mean OS was 49 months for PD-L1-negative patients while for PD-L1-positive patients, it was 43.3 months (p=0.550 Log Rank). Regarding the correlation between PD-L1 expression and NLR value, PFS mean survival times were 13.1 months for PD-L1(+)/NLR>4, 15.1 months for PD-L1(-)/NLR>4, 16.4 months for PD-L1(+)/NLR<4 and 27.8 months for PD-L1(-)/NLR<4. This correlation between PFS and the combined PD-L1 and NLR prognostic factor was statistically relevant (p=0.04). For OS, the PD-L1/NLR combined prognostic factor was not statistically relevant (p=0.055). A mean PFS time of 27.8 months was reported for PD-L1(-)/NLR<4 group patients while for the other groups, the mean PFS was 14.9 months (p=0.045). In univariate analysis, the elevated NLR was significantly associated with a decreased PFS time (HR=2.31, 95% CI =1.323- 4.051, p=0.03) as well as OS (HR=3.555, 95% CI=1.310- 9.652, p=0.013). In multivariate analysis, NLR remained statistically significant for PFS (HR=2.160, 95% CI=1.148- 4.062, p=0.013) and OS (HR=4.364, 95% CI=1.474- 12.921, p=0.008) after adjusting for the factors of age, gender, tumor stage, lymph node stage, clinical stage, histology, and PD-L1 expression. PD-L1 expression was not a valid prognostic factor for progression or death in either univariate or multivariate analysis. We also stratified the disease control rate (DCR) depending on PD-L1/NLR combined factor expression. In the PD-L1(-)/NLR<4 group, we had the highest number of partial responses (PRs) and only one complete response (CR) compared to the other groups (p=0.006). As the number of patients is limited in the present analysis, it is hypothesized that these two markers can be useful in dividing patients into two prognostic groups: the good prognostic group reunites PD-L1(+)/NLR<4 and PD-L1(-)/NLR4 and PD-L1(-)/NLR>4.