Use Of Cyclin-dependent Kinase Research Articles

Clinical use of Abemaciclib a cyclin-dependent kinase (CDK) 4/6 inhibitor in patients with breast cancer — literature review

Breast cancer is the most common neoplasma affecting women. Over, the past few years, the incidence of breast cancer has significantly increased, including among young women. Hormone receptor-positive (HR+) Her2 negative (HER2-) early stage breast cancer can be successfully treated using the currently available treatment methods based on endocrine theraphy (ET). However, if we consider early stage breast cancer with high risk of recurrence or metastatic disease, endocrine therapy alone may be insufficient. Unfortunately, resistance to drugs is observed in both adjuvant and palliative endocrine therapy, therefore there is a need for new treatments that are both effective and less toxic than conventional chemotherapy. One of the most successful applications of this strategy has been the use of cyclin-dependent kinase (CDK) 4 and 6 inhibitors alongside endocrine therapy significantly enhance its effectiveness. This combination has been shown to substantially increase progression-free survival while maintaining relatively low levels of toxicity. One of them is abemaciclib, whose efficacy will be shown in this research work.

Real-World Data with CDK4/6 Inhibitors-A Single Center Experience from Croatia.

There are limited real-world data (RWD) regarding the use of cyclin-dependent kinase (CDK) 4/6 inhibitors in western Balkan. The aim of our study was thus to analyze factors influencing progression-free survival (PFS) and overall survival (OS), along with the differences in adverse effects of CDK 4/6 therapy in a tertiary healthcare center in Croatia. We evaluated medical and demographic data for 163 consecutive patients with metastatic breast cancer treated with CDK4/6 inhibitors for at least one month, from October 2018, after the drug became available in Croatia. Eligible patients in our study were those patients who were treated with palbociclib, ribociclib, or abemaciclib. The median PFS of CDK4/6 inhibitors treatment was 2.2 years (95% CI 1.8-3.3), with the longest ongoing treatment for 5.4 years. Treatment with CDK4/6 inhibitors in the first line was associated with a longer PFS compared to the second line or beyond (HR 0.50, 95% CI 0.3-0.9), and patients without liver metastasis exhibited longer survival compared to patients with liver metastasis (HR 0.46, 95% CI 0.2-0.8) (both p < 0.05). Regarding the choice of CDK4/6 inhibitors, ribociclib exhibited longer PFS compared to palbociclib (HR 0.49, 95% CI 0.29-0.82) (p = 0.0032), although the effect was not statistically significant when separating patients who were treated with CDK4/6 inhibitors in the first-line (HR 0.59, 95% CI 0.29-1.2), or second- or later-line therapy (0.49, 95% CI 0.15-1.55); the trend was present in both lines, however. The presence of liver metastasis (p = 0.04), initial luminal A grade (p = 0.039), and time to metastasis up to 5 years from the initial cancer (p = 0.002) were the only factors that remained statistically significant for PFS in multivariate analysis. Median OS since the diagnosis of metastatic disease was 4.5 years (95% CI 3.9-6.3), median OS since the start of CDK4/6 inhibitors treatment was 3.7 years (95% CI 3.4-4.4), while median OS from initial cancer diagnosis was 15.8 years (95% CI 13.8-18.3). There was no difference in OS based on the choice of CDK4/6 inhibitor (p = 0.44) or the adjuvant hormonal therapy (p = 0.12), although a nonsignificant trend for better OS with ribociclib was present for both regardless of whether it was in first- or second/later-line therapies (p > 0.05). In a multivariate analysis, only the presence of liver metastasis (p = 0.0003) and time to metastasis under 5 years from primary breast cancer (p = 0.03) were associated with a worse OS. Our study provides the RWD with the use of CDK4/6 inhibitors in the treatment of metastatic HR+/HER2- breast cancer. To our best knowledge, there are limited RWD regarding CDK 4/6 inhibitors use in western Balkan; thus, our study provides valuable data from everyday clinical practice for this region of Europe, bridging the gap between randomized clinical trials and clinical reality in western Balkan.

Comment on Giraudo et al. The Use of Cyclin-Dependent Kinase 4/6 Inhibitors in Elderly Breast Cancer Patients: What Do We Know? Cancers 2024, 16, 1838.

In "The Use of Cyclin-Dependent Kinase 4/6 Inhibitors in Elderly Breast Cancer Patients: What Do We Know [...].

Rationale for the Initiation, Outcomes, and Characteristics of Chemotherapy Following CDK4/6 Inhibitors in Breast Cancer: A Real-World Cohort Study.

The standard therapy for hormone-receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer includes the use of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy. The optimal post-CDK4/6i treatment sequence is unclear. This cohort study evaluated the initiation, characteristics, and outcomes of chemotherapy following CDK4/6i-based treatment. Among the 227 patients who began CDK4/6i therapy, 114 completed it. Seventy-nine female patients received further treatment, including 55 receiving chemotherapy. The average age was 60.1 years. Post-CDK4/6i chemotherapy was typically (69.1%) first-line due to an impending visceral crisis. The median progression-free survival (mPFS) was 3.0 months (range 0.5-18.9), and the median overall survival (mOS) was 8.3 months (0.5-26.1). The median OS from the end of CDK4/6i treatment was 12.4 months (1.5-26.8). In univariate analysis, neither mPFS nor mOS was associated with age, tumor grade, receptor status, Ki67 status, time from diagnosis to CDK4/6i cessation, therapy line, or CDK4/6i type. Dose reduction occurred in 12 patients (21.8%), and chemotherapy was ceased due to adverse events in 8 patients (14.6%). Chemotherapy showed limited benefit regardless of the regimen. The role of chemotherapy may evolve with broader CDK4/6i use in adjuvant treatment.

UK multicentre real-world data of the use of cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer

UK multicentre real-world data of the use of cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer

Single institution retrospective review of patients with metastatic hormone receptor positive breast cancer receiving first line therapy of CDK4/6 inhibitors.

e13090 Background: Breast cancer continues to be the most commonly diagnosed cancer in women. The majority of these cancers are estrogen positive (ER+) and about 6% of new cases are stage 4 at time of diagnosis. The current standard of care for postmenopausal women with stage 4 ER+ breast cancer is a combination of an aromatase inhibitor (AI) with a cyclin-dependent kinase (CDK) 4/6 inhibitor. Based on Medicare data claim analysis from IQVIA, CDK 4/6 inhibitors are being used nationally in the first line setting in 56% of cases where 24% of cases were treated with AI monotherapy. The state of Kentucky currently lies below this national average by using this treatment regimen in 38% of cases where 47% of cases are treated with AI monotherapy. The reason for this discrepancy between the national average and Kentucky is currently unknown. To further understanding, we have conducted an internal review of adherence to the guidelines. Methods: This is a single center retrospective study done at University of Louisville, Brown Cancer Center. Data was collected on patients who had biopsy proven metastatic hormone positive breast cancer from July 2021 until May 2023 (n=41). Collected characteristics include age on diagnosis, tumor grade, sites of metastatic disease, first line treatment received, choice of CDK4/6 inhibitor if received, and prior exposure to chemotherapy or anti-estrogen therapy. Results: In our cohort of 41 patients, we found that 63.4% (n=26) of patients received an AI and CDK4/6 inhibitor in the first line. There were 4.88% (n=2) of patients who received AI monotherapy, 21.9% (n=9) received Fulvestrant and CDK4/6 inhibitor, 4.88 % (n=2) received AI and Fulvestrant and 4.88% (n=2) received Fulvestrant alone. In total, patients who received estrogen therapy plus CDK4/6 inhibitor totaled 85% of new patients (n=35). Conclusions: This internal review showed our institution to be compliant with endocrine therapy and CDK 4/6 inhibitor in front-line treatment for the majority of metastatic ER+ patients. Given the supportive data for use of CDK 4/6 inhibitors in front-line treatment, the compliance is expected to be much higher. We recommend continued discussion amongst oncology providers to help identify barriers to treatment and determine the causes for poor compliance in the state of Kentucky.

The Use of Cyclin-Dependent Kinase 4/6 Inhibitors in Elderly Breast Cancer Patients: What Do We Know?

Breast cancer (BC) incidence increases with age, particularly in HR-positive/HER2-negative subtypes. Cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6is) alongside endocrine therapy (ET) have emerged as promising treatments for HR-positive/HER2-negative advanced and early BC. However, their efficacy, safety, and impact on quality of life (QoL) in older and frail patients remain underexplored. This position paper assesses the existing literature from 2015 to 2024, focusing on CDK4/6is use in patients aged 65 years and older with HR-positive/HER2-negative BC. Our analysis methodically addresses critical questions regarding the utilization of CDK4/6is in the elderly BC patient population, organizing findings from the metastatic and adjuvant settings. In the metastatic setting, CDK4/6is significantly improve progression-free survival (PFS), paralleling benefits observed in younger patients, and suggest potential overall survival (OS) benefits, warranting further investigation. Despite an increased incidence of grade ≥ 3 adverse events (AEs), such as neutropenia and asthenia, CDK4/6is present a markedly lower toxicity profile compared to traditional chemotherapy, with manageable side effects. QoL analysis indicates that integrating CDK4/6is into treatment regimens does not significantly impact elderly BC patients' daily life and symptom management. Special attention is given to frail subgroups, and personalized approaches are recommended to balance efficacy and adverse effects, such as starting with ET alone and introducing CDK4/6is upon progression in patients with a low disease burden. Transitioning to the adjuvant setting, early results, particularly with abemaciclib, indicate positive effects on disease-free survival (DFS), emphasizing the need for continued analysis to validate these findings and assess long-term implications. However, data on older patients are insufficient to conclude whether they truly benefit from this treatment. Overall, CDK4/6is present a favorable benefit-risk profile in older BC patients, at least in advanced BC; however, further research is warranted to optimize treatment strategies and improve outcomes in this population.

Use of cyclin-dependent kinase 4 and 6 inhibitors in treating metastatic breast cancer - a year-long experience of Subotica General Hospital in patient follow-up

Introduction. According to GLOBOCAN data from 2020, breast cancer ranks first in the number of newly diagnosed malignancies. The treatment of advanced, hormone-positive breast cancer has evolved with the use of cyclin-dependent kinase 4 and 6 inhibitors in first- and second-line treatment for metastatic, hormone-positive, HER2-negative breast cancers, in combination with endocrine therapy. As of May 31, 2022, these drugs have become available in the Republic of Serbia. This paper aims to present a one-year experience of a secondary health center in monitoring patients using the treatments. Material and Methods. The data analysis included patients treated with cyclin-dependent kinase 4 and 6 inhibitors from June 1, 2022, to June 1, 2023, at General Hospital Subotica. The analysis covered demographic data, disease presentation, previous therapies, drug usage, side effects, duration, and therapy outcomes. Patients were categorized into two groups based on age (&lt;60 and &gt;60 years) and by the nature of their disease (relapsed or initially metastatic). Results. A total of 43 patients were treated with cyclin-dependent kinase 4 and 6 inhibitors: 23 (53.5%) in the first line and 20 (46.5%) in the second line. The median therapy duration was eight cycles for patients younger than 60 years. A good therapeutic response was observed in 53.5% of patients. Patients younger than 60 years with late relapse exhibited statistically significantly better treatment outcomes compared to those older than 60 years (p=0.04). The most common site of metastases was the bones (51%, 22 patients), with half of these patients showing a good therapeutic response. Conclusion. Although the observed period is short, ongoing monitoring and further research are planned to share experiences on the use of these drugs.

Ribociclib-induced visual hallucination in a patient with metastatic breast cancer.

Cyclin-dependent kinase (CDK) 4/6 inhibitors are widely used in combination with aromatase inhibitors or fulvestrant for the treatment of locally advanced or metastatic hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) breast cancer. Hematological toxicities (e.g. neutropenia, thrombocytopenia, anemia, lymphopenia, or febrile neutropenia), infections, decreased appetite, exhaustion, headache, dizziness, cough, nausea, vomiting, diarrhea, alopecia, rash, increased alanine aminotransferase and aspartate aminotransferase levels, and QT interval prolongation are frequent side effects associated with the use of CDK 4/6 inhibitors. However, to our knowledge, no case of hallucination associated with CDK 4/6 inhibitor use has been described in the English-language literature. We report a case of a 72-year-old woman with metastatic breast cancer who developed visual hallucinations after receiving ribociclib, a CDK 4/6 inhibitor, and letrozole for 3 days. Cranial imaging and blood tests did not reveal the cause of the hallucinations. The visual hallucinations completely resolved within 4 days after the ribociclib treatment was terminated. The patient received only letrozole for 2 weeks, and ribociclib treatment was restarted 2 weeks later. Visual hallucinations recurred on the third day of treatment, and ribociclib treatment was discontinued again. The patient recovered completely from visual hallucinations 4 days after discontinuation. Subsequently, treatment was continued with letrozole and palbociclib, another CDK 4/6 inhibitor. Hallucinations did not recur during follow-up. To our knowledge, this is the first reported case of hallucinations caused by ribociclib; notably, it shows that symptoms may develop in the early stage of treatment.

Health-related quality of life of women with breast cancer being treated with hormone therapy: A scoping review.

To map the evidence available in the literature on the health-related quality of life of women with breast cancer using hormone therapy. This review followed the Joanna Briggs Institute methodological recommendations and Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews reporting guidelines. Searches were performed in nine databases using descriptors, synonyms and keywords; grey literature was also included. The review protocol was registered with the Open Science Framework under doi: http://doi.org/10.17605/OSF.IO/347FM. Inclusion criteria were established according to the Population, Concept, and Context strategy. The selection of studies was performed by two independent reviewers with the aid of RAYYAN software and disagreements were resolved by a third reviewer. The main information from the included articles was grouped into textual categories and presented by means of a narrative synthesis. A total of 5419 records were identified, of which 42 studies fully met the eligibility criteria. Most were multicenter studies (42.9%) and randomized controlled trials (62%). Most studies addressed anastrozole (39.5%), letrozole (34.2%), and tamoxifen (26.3%), which were studied alone or in combination. The most widely used health-related quality-of-life assessment tool was the EORTC-QLQ-C30. The concomitant use of hormone therapy and cyclin-dependent kinase inhibitors 4 and 6 showed improvement in health-related quality of life. In recent years there has been an increase in studies focused on health-related quality of life, and the evidence pointed to relevant information on health-related quality of life and the use of endocrine therapy, tamoxifen in combination with aromatase inhibitors, as well as aromatase inhibitor alone and the use of cyclin-dependent kinase 4 and 6.

Regulatory Approval, Reimbursement, and Clinical Use of Cyclin-Dependent Kinase 4/6 Inhibitors in Metastatic Breast Cancer in the Netherlands

This study found that CDK4/6 inhibitors rapidly reached many eligible patients with metastatic breast cancer and were adopted gradually over time in the Netherlands. Adoption of innovative medicines may be further optimized, and better transparency of the availability of new medicines during different phases of the postapproval access pathway is needed. This cohort study reviewed approval and reimbursement decisions of the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib and estimated the number of patients with metastatic breast cancer who were eligible for these medicines compared with the actual use in clinical practice. The study used nationwide claims data that were obtained from the Dutch Hospital Data. Claims and early access data for patients with hormone receptor-positive and ERBB2 (formerly HER2)-negative metastatic breast cancer who were treated with CDK4/6 inhibitors from November 1, 2016, to December 31, 2021, were included. The number of new cancer medicines that are being approved by regulatory agents is increasing exponentially. Yet little is known about the pace at which these medicines reach eligible patients in daily clinical practice during different phases of the postapproval access pathway. Description of the postapproval access pathway, monthly number of patients who were treated with CDK4/6 inhibitors in clinical practice, and estimated number of patients who were eligible for treatment. Aggregated claims data were used, and patient characteristics and outcomes data were not collected. To describe the entire postapproval access pathway of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in the Netherlands, from regulatory approval to reimbursement and to investigate the adoption of these medicines in clinical practice among patients with metastatic breast cancer. Three CDK4/6 inhibitors have received European Union-wide regulatory approval for the treatment of HR-positive and ERBB2-negative metastatic breast cancer since November 2016. In the Netherlands, the number of patients who have been treated with these medicines increased to approximately 1847 (based on 1 624 665 claims over the entire study period) from approval to the end of 2021. Reimbursement for these medicines was granted between 9 and 11 months after approval. While awaiting reimbursement decisions, 492 patients received palbociclib, the first approved medicine of this class, via an expanded access program. By the end of the study period, 1616 patients (87%) were treated with palbociclib, whereas 157 patients (7%) received ribociclib, and 74 patients (4%) received abemaciclib. The CKD4/6 inhibitor was combined with an aromatase inhibitor in 708 patients (38%) and with fulvestrant in 1139 patients (62%). The pattern of use over time appeared to be somewhat lower compared with the estimated number of eligible patients (1847 vs 1915 in December 2021), especially in the first 2.5 years after approval.

Vitiligo-like lesions associated with ribociclib in a woman with metastatic breast cancer.

Cyclin-dependent kinase 4/6 inhibitors are new generation drugs that have recently been used in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negativenegative metastatic breast cancer. Recent studies have shown that the use of cyclin-dependent kinase 4/6 inhibitors significantly improves the outcomes of these patients. The most common side effects of cyclin-dependent kinase 4/6 inhibitors are hematological toxicity, gastrointestinal side effects, and fatigue. We aimed to present a case of metastatic breast cancer who was treated with ribociclib and developed vitiligo-like lesions after treatment. A 56-year-old female patient was diagnosed with locally advanced hormone receptor (+)/human epidermal growth factor receptor 2 (-) breast cancer in May 2000. She was followed up with hormonal therapy after adjuvant chemotherapy and radiotherapy. The patient progressed with lung metastases in 2012. Ribociclib, anastrozole, and leuprolide acetate were started in November 2021 after multiple-line chemotherapy. After six cycles of ribociclib, vitiligo-like lesions that developed in the last 1 month were detected on the upper extremities, both hands, neck, chest, and upper back. The patient was referred to dermatology. Topical immunosuppressive therapy and oral corticosteroids were recommended. At the first and third-month follow-up examinations, vitiligo-like lesions were observed to persist. Vitiligo-like lesions are not a life-threatening side effect. However, it significantly affects the quality of life and disrupts the patient's compliance with treatment. Cyclin-dependent kinase 4/6 inhibitors can inhibit cell division or cause premature cell death by acting on the melanocyte cell cycle.

Genomic Aberrations in Circulating Tumor DNAs from Palbociclib-Treated Metastatic Breast Cancer Patients Reveal a Novel Resistance Mechanism.

Simple SummaryThe combination of CDK4/6 inhibitors and endocrine therapy is now considered the standard of care for patients with estrogen receptor-positive (ER+) breast cancer. The emerging tide of CDK4/6 inhibitor resistance urges more research to explore underlying resistance mechanisms. This study profiled circulating cell-free DNA obtained before and after palbociclib treatment in ER+ metastatic breast cancer patients using 91-gene panel sequencing. The results revealed that the acquisition of CCNE1 mutations and the loss of TSC2 mutations confer an unfavorable prognosis, suggesting that these mutations may potentially serve as novel genomic biomarkers for treatment resistance. Future large-scale population studies and mechanism-focused research are needed to confirm the findings of this study and elucidate the underlying molecular mechanisms. Ultimately, such efforts may lead to the development of improved methods to predict treatment efficacy and clinical outcomes, as well as more effective targeted treatment approaches for the benefit of breast cancer patients.Previously undescribed molecular mechanisms of resistance will emerge with the increased use of cyclin-dependent kinase 4/6 inhibitors in clinical settings. To identify genomic aberrations in circulating tumor DNA associated with treatment resistance in palbociclib-treated metastatic breast cancer (MBC) patients, we collected 35 pre- and post-treatment blood samples from 16 patients with estrogen receptor-positive (ER+) MBC, including 9 with inflammatory breast cancer (IBC). Circulating cell-free DNAs (cfDNAs) were isolated for sequencing using a targeted panel of 91 genes. Our data showed that FBXW7 and CDK6 were more frequently altered in IBC than in non-IBC, whereas conversely, PIK3CA was more frequently altered in non-IBC than in IBC. The cfDNA samples collected at follow-up harbored more mutations than baseline samples. By analyzing paired samples, we observed a higher percentage of patients with mutations in RB1, CCNE1, FBXW7, EZH2, and ARID1A, but a lower proportion of patients with mutated TSC2 at the post-treatment stage when they developed progression. Moreover, acquisition of CCNE1 mutations or loss of TSC2 mutations after treatment initiation conferred an unfavorable prognosis. These data provide insights into the relevance of novel genomic alterations in cfDNA to palbociclib resistance in MBC patients. Future large-scale prospective studies are warranted to confirm our findings.

PostMONARCH: A phase 3 study of abemaciclib plus fulvestrant versus placebo plus fulvestrant in patients with HR+, HER2-, metastatic breast cancer following progression on a CDK4 &amp; 6 inhibitor and endocrine therapy.

TPS1117 Background: The use of cyclin dependent kinase 4 and 6 (CDK4 &amp; 6) inhibitors plus endocrine therapy (ET) has transformed the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). However, most patients will experience disease progression. Identification of treatment options following progression is an unmet medical need. Additionally, as CDK4 &amp; 6 inhibitors are now being deployed in the adjuvant setting, determination of optimal therapy following metastatic relapse is an important question. In patients with disease progression following a CDK4 &amp; 6 inhibitor-based regimen, continuing CDK4 &amp; 6 inhibition with abemaciclib while switching the ET backbone may provide benefit and delay the need for cytotoxic chemotherapy. Abemaciclib is an oral, selective, and potent CDK4 &amp; 6 inhibitor administered continuously and approved as monotherapy or with ET for treatment of HR+, HER2- ABC. Abemaciclib has also been approved with ET for the adjuvant treatment of HR+, HER2-, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score ≥20%. Fulvestrant is a selective ER degrader (SERD) approved for treatment of HR+, HER2- ABC. The postMONARCH study investigates whether abemaciclib plus fulvestrant will improve outcomes in patients with HR+, HER2- ABC after disease relapse or progression after adjuvant or first-line treatment with a CDK4 &amp; 6 inhibitor plus ET. Methods: postMONARCH is a Phase 3, global, multicenter, randomized, double-blind, placebo-controlled study in patients with HR+, HER2- ABC and with disease progression on treatment with a prior CDK4 &amp; 6 inhibitor plus an aromatase inhibitor as initial therapy for ABC or recurrence on/after treatment with a CDK4 &amp; 6 inhibitor plus ET in the adjuvant setting. Eligible patients are randomized 1:1 to receive abemaciclib 150 mg twice daily or placebo, plus fulvestrant. Stratification factors include geography, presence of visceral metastasis, and duration of prior CDK4 &amp; 6 inhibitor-based regimen. The study is powered at 80% with a cumulative Type I error of 0.025 to detect the superiority of abemaciclib plus fulvestrant versus placebo plus fulvestrant in terms of investigator-assessed progression free survival. Key secondary endpoints include overall survival, PFS by blinded independent central review, objective response rate, safety, patient-reported outcomes, and pharmacokinetics. This study opened in Jan 2022, plans for approximately 122 centers in 18 countries, and anticipates enrolling ̃350 patients. Clinical trial information: NCT05169567.

Impact of the COVID-19 Pandemic on Breast Cancer Management in Portugal: A Cross-Sectional Survey-Based Study of Medical Oncologists.

IntroductionCancer care providers have faced many challenges in delivering safe care for patients during the COVID-19 pandemic. This cross-sectional survey-based study investigated the impact of the pandemic on clinical practices of Portuguese medical oncologists caring for patients with breast cancer.MethodsAn anonymous online survey comprising 42 questions gathered information regarding COVID-19 testing, treatment in (neo)adjuvant and metastatic settings, and other aspects of breast cancer management. Practices before and during the pandemic were compared, and potential differences in outcomes according to respondents’ regions, case volumes, and practice type were explored.ResultsOf 129 respondents, 108 worked in the public health system, giving a representative national picture of the impact of the COVID-19 pandemic on breast cancer management. Seventy-one percent of respondents reported a reduction in visits for new cases of breast cancer, and there was a shift towards increased use of telemedicine. Clinical decision-making was largely unaffected in the most aggressive indications (i.e., triple-negative, HER2-positive, visceral crisis). The use of neoadjuvant therapy increased when access to surgery was difficult, whereas dose-dense regimens decreased, and cyclin-dependent kinase 4/6 inhibitor treatment decreased for less aggressive disease and increased for more aggressive disease. The use of oral formulations and metronomic chemotherapy regimens increased, and clinical trial participation decreased. Some differences by respondents’ region and case volume were noted.ConclusionMedical oncologists in Portugal implemented many changes during the COVID-19 pandemic, most of which were logical and reasonable responses to the current healthcare emergency; however, the true impact on patient outcomes remains unknown.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40487-022-00191-7.

Adjuvant cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive breast cancer: One Monarch to rule them all?

The use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has dramatically improved outcomes for patients with metastatic, hormone receptor (HR)-positive breast cancer. Because of the continued high rate of relapse in patients with node-positive, HR-positive disease, evaluating these agents in the adjuvant setting is the logical next step. Three adjuvant CDK inhibitor trials have been reported to date, with only 1 of them showing a statistical advantage for the CDK inhibitor in comparison with endocrine therapy alone. These trials have key similarities and differences that could explain the disparate results. The one positive trial has a relatively short follow-up, and continued analysis is critical to confirm the benefit of adjuvant CDK inhibition in this setting. It is imperative that predictive biomarkers be determined so that these agents can be used in the patients most likely to benefit and thus the additional toxicity and expense can be avoided in those who do not require these agents. LAY SUMMARY: There is a critical need for new agents to prevent relapse in patients with hormone receptor-positive breast cancer. Trials to date evaluating cyclin-dependent kinase inhibitors, which decrease how quickly cancer cells multiply, have shown mixed results, with only 1 trial demonstrating that these agents decrease recurrence.

Combination of Talazoparib and Palbociclib as a Potent Treatment Strategy in Bladder Cancer

The use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors represents a potent strategy for cancer therapy. Due to the complex molecular network that regulates cell cycle progression, cancer cells often acquire resistance mechanisms against these inhibitors. Previously, our group identified molecular factors conferring resistance to CDK4/6 inhibition in bladder cancer (BLCA) that also included components within the DNA repair pathway. In this study, we validated whether a combinatory treatment approach of the CDK4/6 inhibitor Palbociclib with Poly-(ADP-Ribose) Polymerase (PARP) inhibitors improves therapy response in BLCA. First, a comparison of PARP inhibitors Talazoparib and Olaparib showed superior efficacy of Talazoparib in vitro and displayed high antitumor activity in xenografts in the chicken chorioallantoic membrane (CAM) model. Moreover, the combination of Talazoparib and the CDK4/6 inhibitor Palbociclib synergistically reduced tumor growth in Retinoblastoma protein (RB)-positive BLCA in vitro and in a CAM model, an effect that relies on Palbociclib-induced cell cycle arrest in G0/G1-phase complemented by a G2 arrest induced by Talazoparib. Interestingly, Talazoparib-induced apoptosis was reduced by Palbociclib. The combination of Palbociclib and Talazoparib effectively enhances BLCA therapy, and RB is a molecular biomarker of response to this treatment regimen.

ESMO20 YO for YO: highlights on adjuvant CDK4/6 inhibitors in early hormone receptor-positive/HER2-negative breast cancer

ESMO20 virtual conference brought us the results of two major randomized trials on the adjuvant use of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for early hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer (BC). The two studies, PALLAS with palbociclib (ClinicalTrials.gov identifier NCT02513394) and monarchE with abemaciclib (NCT03155997), reported conflicting results. In the latter, adding abemaciclib for 2 years to standard endocrine therapy improved both the primary endpoint, invasive disease-free survival (DFS) with an absolute improvement of 3.5% at 2 years, as well as distant relapse-free survival (DRFS) with an absolute improvement of 3.3% at 2 years.

Concurrent Use of Cyclin Dependent Kinase 4/6 (CDK4/6) Inhibitors with Palliative Radiotherapy for Metastatic Breast Cancer Patients: A Review of Toxicity

Concurrent Use of Cyclin Dependent Kinase 4/6 (CDK4/6) Inhibitors with Palliative Radiotherapy for Metastatic Breast Cancer Patients: A Review of Toxicity

P139: Uptake of Cyclin Dependant Kinase 4/6 inhibitors (CDKi) - A retrospective audit at University Hospital Birmingham trust (UHB) (audit approval number: Carms15507)

Introduction: Since 2017, NICE has approved the first line use of Cyclin Dependent Kinase 4/6 Inhibitors (CDKis) for hormone receptor positive and HER2 negative locally advanced (LABC) or metastatic breast cancer (MBC). Uptake amongst units is variable. CDKis are currently only licensed in conjunction with an aromatase inhibitor or Fulvestrant. Alternative treatments include endocrine monotherapy and/or chemotherapy. This retrospective audit aims to quantify the uptake of CDKis at University Hospital Birmingham (UHB) Trust, and assess variations, if any, compared to the expected uptake of 60% determined by NICE.