UNASSIGNED: There is no clear information in the literature about the relationship between the efficacy of CDK 4/6i combined with ET and HR positivity. However, we know that the longest overall survival was in the ER-strong positive/PR intermediate or strong positive groups. Therefore, we aimed to investigate CDK4/6i treatments that create positivity in HR.
UNASSIGNED: Patients with the diagnosis of HR+/HER2- MBC who were treated with CDK 4/6i and HR >10% were retrospectively evaluated. To analyze the role of HR positivity, ER was moderately positive (10-49%) and ER was strongly positive (50-100%); PR was grouped as moderately positive (10-49%) and PR strongly positive (50-100%).
UNASSIGNED: Median follow-up of 150 patients included in the study was 15.2 months (95% CI, 2.1-40.9 months). The highest response in the whole group was obtained in the ER-strong positive/PR moderate or strong positive group, and the ER moderate positive/PR moderate or strong group. This was followed by the ER strong positive/PR negative group, and then the ER moderate positive/PR negative group. Although these advantages were not statistically significant, they were numerically higher (ORR: 83.8% vs. 83.3% vs. 77.4% vs. 62.5%, p=0.488, respectively). The highest survival in the whole group was achieved in the ER strong positive/PR moderate or strongly positive group, followed by the ER moderately positive/PR moderate or strongly positive group, the ER strongly positive/PR negative group followed by the ER moderate positive/PR negative group, respectively(p=0.410). However, these advantages were not statistically significant.
UNASSIGNED: As a result, HR+/HER2- MBC patients receiving CDK 4/6i combined with ET suggest that the percentage of HR positivity may have a predictive and prognostic role.

OBJECTIVE: Human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) is a new entity considered a biologically distinct subtype from HER2-zero BC. However, the importance of HER2 low expression on the activity of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) remains unclear.
METHODS: We conducted a single-center retrospective study including hormone receptor-positive (HR +) /HER2- metastatic BC (mBC) patients treated with CDK4/6i plus endocrine treatment (ET) as first-line therapy. Clinical outcomes were analyzed according to HER2 expression.
RESULTS: 258 women were analyzed with a median follow-up of 25.4 months; 39.9% had HER2 low, and 60.1% had HER2 zero BC. Median progression-free survival (mPFS) in the HER2-low group was 27.6 months compared with 44.3 months in the HER2-zero group (p = 0.341). In patients receiving ribociclib, the mPFS in the HER2-low group was 24.2 months compared with 53.1 months in the HER2-zero group (multivariate-adjusted HR: 1.981, 95 Cl 1.094-3.586; p = 0.024). The survival probabilities at 24, 36 and 48 months for the HER2 low and HER2 zero groups were 82%, 69%, 69% and 83%, 75% and 69%, respectively (p = 0.336). Objective response rate (p = 0.179) and disease control rate (p = 0.338) did not significantly differ between HER-2-low and HER-2-zero groups.
CONCLUSIONS: The mPFS in the Her2-zero group was almost twice that of the Her2-low group, but the difference was not statistically significant. mPFS was significantly longer in the HER2-zero group compared to the HER2-low group in patients receiving ribociclib. More prospective studies are needed to understand the actual consequences of this biomarker.

UNASSIGNED: Idiosyncratic drug-induced liver injury (DILI) is a rare, unpredictable hepatic adverse event and the most common cause of acute liver failure in Europe and the US. Ribociclib is a potent Cyclin-dependent kinase 4 and 6 (CDK4/6)-inhibitor administered for advanced hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Previous reports have shown hepatotoxicity without liver necrosis related to ribociclib.
UNASSIGNED: A 41-year-old female patient with primary metastatic HR-positive, HER2-negative breast cancer developed liver enzyme elevation under treatment with ribociclib. Ribociclib was withdrawn 8 weeks after initiation due to liver enzyme elevation. A liver biopsy, performed due to further enzyme increase (peak ALT 2836 U/l), onset of jaundice (peak bilirubin 353 µmol/l) and coagulopathy (INR 1.8) two weeks later, revealed acute hepatitis with 30% parenchymal necrosis. Roussel Uclaf Causality Assessment Method (RUCAM) score was 7 points (probable). Under treatment with prednisone (60mg), initiated 2 weeks after drug withdrawal, and subsequently N-acetylcysteine (Prescott regimen) liver enzymes normalized within 8 weeks along with prednisone tapering.
UNASSIGNED: This case illustrates the development of a severe idiosyncratic hepatocellular pattern DILI grade 3 (International DILI Expert Working Group) induced by ribociclib. Routine liver enzyme testing during therapy, immediate hepatologic work-up and treatment interruption in case of liver enzyme elevation are highly recommended. Corticosteroid treatment should be considered in cases of severe necroinflammation.

BACKGROUND: Efficacy and quality of life (QoL) are key criteria for therapy selection in metastatic breast cancer (MBC). In hormone receptor positive (HR +) human epidermal growth factor receptor 2 negative (HER2 -) MBC, addition of targeted oral agents such as everolimus or a cycline-dependent kinase 4/6 (CDK 4/6) inhibitor (e.g., palbociclib, ribociclib, abemaciclib) to endocrine therapy substantially prolongs progression-free survival and in the case of a CDK 4/6i also overall survival. However, the prerequisite is adherence to therapy over the entire course of treatment. However, particularly with new oral drugs, adherence presents a challenge to disease management. In this context, factors influencing adherence include maintaining patients\' satisfaction and early detection/management of side effects. New strategies for continuous support of oncological patients are needed. An eHealth-based platform can help to support therapy management and physician-patient interaction.
METHODS: PreCycle is a multicenter, randomized, phase IV trial in HR + HER2 - MBC. All patients (n = 960) receive the CDK 4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. PreCycle evaluates and compares the time to deterioration (TTD) of QoL in patients supported by eHealth systems with substantially different functionality: CANKADO active vs. inform. CANKADO active is the fully functional CANKADO-based eHealth treatment support system. CANKADO inform is a CANKADO-based eHealth service with a personal login, documentation of daily drug intake, but no further functions. To evaluate QoL, the FACT-B questionnaire is completed at every visit. As little is known about relationships between behavior (e.g., adherence), genetic background, and drug efficacy, the trial includes both patient-reported outcome and biomarker screening for discovery of forecast models for adherence, symptoms, QoL, progression free survival (PFS), and overall survival (OS).
CONCLUSIONS: The primary objective of PreCycle is to test the hypothesis of superiority for time to deterioration (TTD) in terms of DQoL = \"Deterioration of quality of life\" (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in patients merely receiving eHealth-based information (CANKADO inform). EudraCT Number: 2016-004191-22.

UNASSIGNED: The identification of the novel targeted therapy i.e., cyclin-dependent kinases (CDKs) 4/6 inhibitor as combined with the endocrine regimen revealed a considerable capability to increase the managements\' effectivity of hormone-receptor-positive (HR+) and HER2- breast cancer (BC).
UNASSIGNED: This study aims to compare the latter combination strategies versus hormonal therapy alone to determine its applicability in the treatment of HR+/HER2- BC.
UNASSIGNED: We established the review based on the clinical trials as collected from several scientific databases from January 2011 to April 2021. RevMan 5.4 was utilized in statistical analysis and risk of bias (RoB) measurement. 5110 participants from 9 different trials were included in this review with similar baseline characteristics.
UNASSIGNED: According to our analysis of the intention-to-treat (ITT) group, CDK 4/6 inhibitor arms exhibited better overall response rate (ORR) as indicated by the relative risk (RR) (randomized-effect model (REM), 1.59 [1.37, 1.86]; 95% confidence interval (CI); P <0.00001) and higher clinical benefit rate (CBR) (RR, 1.22 [1.13, 1.32]; 95% CI; REM; P <0.00001). The combination regiment also proved to be effective in reducing the rate of progressive disease (PD) in the ITT group (RR 0.46 [0.39, 0.54]; CI 95%; FEM; P <0.00001. Although the rate of adverse effects especially the hematological reactions was significantly lower in the endocrine alone arm, other system reactions were fairly comparable.
UNASSIGNED: The introduction of CDK 4/6 inhibitor to the endocrine-based regiment is proved beneficial to patients with HR+/HER2- BC even though the most recommended anti-hormonal to be combined remains questionable.

Aim: To demonstrate the prognostic importance of glucose-to-lymphocyte ratio (GLR) and uric acid (UA) in patients with metastatic breast cancer (MBC) receiving Cdk 4/6 inhibitors. Materials & methods: Neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, GLR, UA and CA15-3 were analyzed to assess their prognostic value using Kaplan-Meier curves and Cox regression analysis in 101 patients with MBC, retrospectively. Results: Importantly, both progression-free survival and overall survival were shorter in the group with high neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), GLR and UA. In the multivariate analysis, GLR and UA levels were independent prognostic factors for both progression-free survival and overall survival. Conclusion: In patients with MBC, GLR and UA are independent factors that predict survival times.
Some studies on solid organ malignancies have shown the predictive importance of the glucose-to-white blood cell count ratio obtained by dividing blood sugar by the lymphocyte count and uric acid (UA) resulting from protein metabolism. This study aimed to investigate the predictive significance of the glucose-to-white blood cell count ratio and UA in blood before the use of Cdk inhibitors in patients with hormone receptor-positive and HER2-negative metastatic breast cancer. The results show that higher glucose-to-white blood cell count ratio and UA are associated with survival parameters and serve as independent predictive factors for shorter progression-free survival, disease-free survival and overall survival. Thus, glucose-to-white blood cell count ratio and UA can be used to better predict the survival and prognosis of patients using Cdk inhibitors.

OBJECTIVE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), in combination with endocrine therapy (ET), are standard either in the first (1L) or second-line (2L) setting for the treatment of hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC). However, the optimal sequencing of treatments after progression on CDK4/6i remains unknown. We performed a single-institution analysis to identify treatments and outcomes after progression on a CDK4/6i.
METHODS: We identified patients with HR-positive, HER2-negative MBC prescribed a CDK4/6i in the 1L or 2L settings from December 2014 to February 2018 at Mayo Clinic in Rochester, Minnesota. Outcomes were collected through September 30, 2020.
RESULTS: Palbociclib, in combination with letrozole or fulvestrant, was the most prescribed CDK4/6i. The 1L and 2L CDK4/6i cohorts exhibited comparable overall survival (OS), but progression-free survival (PFS) was longer in the 1L than the 2L cohort [28.2 months (95% CI 19.6-34.9) vs 19.8 months (95% CI 15.7-29.6)]. The most common post-CDK4/6i treatments were PI3K/mTOR inhibitors (PI3K/mTORi), single-agent ET, or chemotherapy. PFS in the 1L CDK4/6i cohort following PI3K/mTORi was 8.5 months (95% CI 5.5 months-NE), single-agent ET was 6.0 months (95% CI 3.3-14.0 months), and chemotherapy PFS was 5.4 months (95% CI 3.3 months-NE).
CONCLUSIONS: Following progression on a CDK 4/6i, mPFS was short, with similar PFS times comparing chemotherapy and ET, with slightly longer PFS for targeted strategies (PI3K/mTOR). These results highlight a major need to better understand the mechanisms of CDK4/6i resistance and identify new therapeutic strategies for these patients.

Cyclin-dependent kinase 4/6 inhibitors are the standard of care for hormone receptor-positive metastatic breast cancer. This retrospective study reports on genomic biomarkers of CDK 4/6i resistance utilizing genomic data acquired through routine clinical practice. Patients with HR+ MBC treated with palbociclib, ribociclib, or abemaciclib and antiestrogen therapy were identified. Patients were grouped into early (<6 months); intermediate (6−24 months for 0−1 lines; 6−9 months for ≥2 lines); or late progressors (>24 months for 0−1 lines; >9 months PFS for ≥2 lines). NGS and RNA sequencing data were analyzed in association with PFS, and survival analysis was stratified by prior lines of chemotherapy. A total of 795 patients with HR+ MBC treated with CDK 4/6i were identified. Of these, 144 (18%) patients had genomic data and 29 (3.6%) had RNA data. Among the 109 patients who received CDK4/6i as 1st- or 2nd-line therapy, 17 genes showed associations with PFS (p-value ≤ 0.15 and HR ≥ 1.5 or HR < 0.5). Whole transcriptome RNAseq was analyzed for 24/109 (22%) patients with 0−1 prior lines of therapy and 56 genes associated with PFS (HR ≥ 4 or HR ≤ 0.25 and FDR ≤ 0.15). In this retrospective analysis, genomic biomarkers including FGFR1 amplification, PTEN loss, and DNA repair pathway gene mutations showed significant associations with shorter PFS for patients receiving CDK4/6 inhibitor therapy.

Approximately 20% of invasive breast cancers have upregulation/gene amplification of the oncogene human epidermal growth factor receptor-2 (HER2/ErbB2). Of these, some also express steroid receptors (the so-called Luminal B subtype), whereas others do not (the HER2 subtype). HER2 abnormal breast cancers are associated with a worse prognosis, chemotherapy resistance, and sensitivity to selected anti-HER2 targeted therapeutics. Transcriptional data from over 3000 invasive breast cancers suggest that this approach is overly simplistic; rather, the upregulation of HER2 expression resulting from gene amplification is a driver event that causes major transcriptional changes involving numerous genes and pathways in breast cancer cells. Most notably, this includes a shift from estrogenic dependence to regulatory controls driven by other nuclear receptors, particularly the androgen receptor. We discuss members of the HER receptor tyrosine kinase family, heterodimer formation, and downstream signaling, with a focus on HER2 associated pathology in breast carcinogenesis. The development and application of anti-HER2 drugs, including selected clinical trials, are discussed. In light of the many excellent reviews in the clinical literature, our emphasis is on recently developed and successful strategies to overcome targeted therapy resistance. These include combining anti-HER2 agents with programmed cell death-1 ligand or cyclin-dependent kinase 4/6 inhibitors, targeting crosstalk between HER2 and other nuclear receptors, lipid/cholesterol synthesis to inhibit receptor tyrosine kinase activation, and metformin, a broadly inhibitory drug. We seek to facilitate a better understanding of new approaches to overcome anti-HER2 drug resistance and encourage exploration of two other therapeutic interventions that may be clinically useful for HER+ invasive breast cancer patients.

BACKGROUND: Resistance to endocrine therapy has been a major obstacle in the management of hormone receptor (HR)-positive metastatic breast cancer (MBC). Meanwhile, a number of treatments are available to such patients, and physicians often encounter difficulties in choosing the most appropriate treatments for individual patients. The combination of CDK 4/6 inhibitors (CDKi) and endocrine therapy has now become a standard treatment for HR-positive and human epidermal growth factor receptor 2 (HER2)-negative MBC. However, no predictive markers for CDKi-based treatments have been established. Considering their side effects and the financial burden on patients, identifying such markers is crucial.
METHODS: Clinicopathological features of 107 patients with HR-positive HER2-negative MBC, who received CDKi-based treatments at our institution were retrospectively investigated. HR status in distant metastatic lesions and immunocompetent cells in peripheral blood were also studied.
RESULTS: Progression-free survival (PFS) was significantly shorter in patients whose primary tumour was high grade (P = 0.016) or high neutrophil-to-lymphocyte ratio (NLR) at baseline (P = 0.017). Meanwhile, there were no differences in other factors, such as expression levels of hormone receptors. Patients whose metastatic lesions were of low tumour grade or high Ki67 labelling index had longer PFS, and such trends were more obvious than primary lesions.
CONCLUSIONS: Our data indicate that tumour grade in primary lesion and NLR are potential predictive factors for CDKi-based treatments. Moreover, pathological assessment of metastatic lesions might also be useful.