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1.
Int Cancer Conf J ; 13(4): 471-475, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39398903

RESUMO

Abemaciclib (ABM) is recommended for adjuvant endocrine therapy in hormone receptor-positive, human epidermal growth factor receptor type 2-negative early breast cancer (EBC) patients at high risk of recurrence. Here, we present a case of radiation hepatitis challenging to differentiate from drug-induced liver injury during ABM treatment. The patient, a woman in her 40 s, underwent right mastectomy, axillary dissection, and postmastectomy radiation therapy (PMRT) after neoadjuvant chemotherapy for EBC. Subsequently, she received ABM as adjuvant endocrine therapy. Despite suspending ABM due to Grade 3 leukopenia, she developed Grade 3 hepatic dysfunction upon cessation. Based on the dynamic contrast-enhanced computed tomography, we diagnosed the cause of liver dysfunction as radiation hepatitis. Spontaneous improvement allowed us to resume ABM treatment. Clinicians may need to consider radiation hepatitis as a potential cause of hepatic dysfunction in patients who underwent PMRT, along with drug-induced liver injury.

2.
Breast ; 78: 103815, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39413680

RESUMO

BACKGROUND: This paper aimed to evaluate the effectiveness of incorporating CDK 4/6 inhibitors (CDK4/6i) into ET for the adjuvant treatment of HR + HER2-resected early-stage breast cancer (ESBC) patients, employing meta-analysis. METHODS: In this paper, we compiled randomized clinical trials focusing on CDK4/6i used in the adjuvant treatment of high-risk invasive HR-positive and HER2-ESBC patients. A meta-analysis was performed in line with the PRISMA guidelines. RESULTS: We identified four clinical trials that met our inclusion criteria and were published between 2020 and 2024. These trials involved a combined sample size of 17,749 patients diagnosed with breast cancer. The data obtained from the pooled analysis revealed a remarkable beneficial trend in terms of invasive disease-free survival (iDFS) for the use of ET in combination with CDK4/6i compared to the group receiving ET alone (HR = 0.81, 95 % CI: 0.67-0.98, p = 0.03). Of note, CDK4/6 inhibitors demonstrated a notably beneficial effect in both grade 2 (HR = 0.69, 95 % CI: 0.59-0.81, p < 0.001) and grade 3 (HR = 0.76, 95 % CI: 0.65-0.89, p < 0.001). Significant improvements were noted in terms of distant relapse-free survival (dRFS) in the groups treated with abemaciclib and ribociclib (HR = 0.65, 95 % CI: 0.56-0.76, p < 0.001; HR = 0.72, 95 % CI: 0.58-0.89, p = 0.003, respectively). CDK4/6i didn't yield a statistically significant difference in overall survival (OS) (HR = 0.96, 95 % CI: 0.77-1.19, p = 0.69). The use of CDK4/6i with ET was associated with an increased risk of adverse events, particularly anemia and neutropenia, compared with ET alone (OR = 9.12, 95 % CI = 5.04-16.48, p < 0.001). CONCLUSION: The findings of this paper demonstrate a significant improvement in iDFS when ET is combined with CDK4/6i, compared to ET alone. Specifically, treatments with abemaciclib and ribociclib showed notable enhancements in dRFS.

3.
Cancers (Basel) ; 16(19)2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39409937

RESUMO

Background: Despite early diagnosis, approximately 20% of patients with ER-positive and HER2-negative breast cancer (BC) will experience disease recurrence. Improved survival has been reported with adjuvant treatment combining cyclin-dependent kinase 4/6 inhibitors with endocrine therapy, in high-risk patients with ER-positive and HER2-negative BC, regardless of age. Older patients have higher rates of ER-positive/HER2-negative BC than younger patients. Methods: In this real-world data analysis, MonarchE and NataLEE high-risk patients accounted for 9.5% and 33% of patients undergoing upfront surgery, respectively. Significantly higher eligibility rates were observed in patients who underwent a mastectomy, >70 years and ≤40 years for adjuvant abemaciclib and ribociclib, and in patients >80 years for ribociclib. Results: Eligibility rates in patients ≤40 years and >80 years who underwent mastectomy were 27.8% and 24.7% for abemaciclib, respectively, and 56.6% and 65.2% for ribociclib, respectively. A higher discontinuation rate for abemaciclib was reported in patients aged ≥65 years and it can be assumed that discontinuation rates may increase in even older patients. Conclusions: If the results of the NataLEE trial translate into clinical practice, the number of patients potentially eligible for adjuvant CDK4/6 inhibitors may increase, especially in the elderly population.

4.
Oncologist ; 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39419769

RESUMO

BACKGROUND: Real-world data are limited for patients with brain metastases secondary to metastatic breast cancer (MBC) and treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). This study describes real-world outcomes in patients with hormone receptor-positive, human epidermal growth factor 2-negative (HR+/HER2-) MBC with brain metastases diagnosis before abemaciclib initiation. PATIENTS AND METHODS: A nationwide electronic health record-derived de-identified MBC database (January 2011-December 2021) was assessed retrospectively. Patients with HR+/HER2- MBC who were treated with abemaciclib (monotherapy or in combination) following diagnosis of brain metastases were included. Real-world best response reflected clinician-documented response assessment of the brain imaging (intracranial) and change in disease burden following radiographic imaging (extracranial); these were reported descriptively. Time to treatment discontinuation (TTD), real-world progression-free survival (rwPFS), and overall survival (rwOS) were assessed using Kaplan-Meier methods from abemaciclib initiation (index date). RESULTS: Among 82 included patients (mean age 57.0 years; 98.8% female), 22.0% and 19.5% received CDK4/6i and chemotherapy before abemaciclib initiation, respectively, and the majority (80.5%) received radiation/local surgery to the brain before abemaciclib initiation. Patients mostly received abemaciclib as monotherapy (n = 6) or in combination with endocrine therapy (n = 68). Median TTD was 7.1 (95% CI 4.6-11.3) months, rwPFS was 9.2 (95% CI 6.0-11.6) months, and rwOS was 20.8 (95% CI 13.9-26.0) months. Intracranial and extracranial objective response rates, as determined by treating physicians, were 45.1% (n = 23/51) and 56.7% (n = 34/60), respectively. Intracranial and extracranial clinical benefit rates were 62.7% (n = 32/51) and 70.0% (n = 42/60), respectively. CONCLUSION: In this real-world study of patients diagnosed with brain metastases and initiating abemaciclib, most patients received radiation/local surgery to the brain before abemaciclib initiation. Although the outcomes in this real-world study are encouraging, it is unclear if the benefit was due to local therapy, abemaciclib, or the combination, and causality cannot be inferred. Further prospective clinical studies are needed to confirm the clinical benefit of this approach.

5.
Clin Transl Oncol ; 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39436622

RESUMO

INTRODUCTION: Bladder cancer is one of the most common malignancies of the urinary system and there's a significant unmet need for new effective therapeutics for bladder cancer. The limited number of available models to study malignant bladder tumors is one of the obstructions in developing bladder cancer therapeutics. Patient-derived xenograft (PDX) and organoid (PDO) models are more representatives of human cancer than cell lines and cell line-derived xenograft (CDX) and are likely to be more promising and efficient in predicting drug response and finding new therapeutics. METHODS: Three pairs of patient-derived xenograft (PDX) models of bladder cancer and their corresponding PDX-derived organoids (PDXOs) were successfully established. These models were utilized to assess the efficacy of abemaciclib. The sensitivity of the drug was determined through the Cell Counting Kit-8 (CCK8) assay in PDXO cultures, corroborated by the EdU incorporation assay. Additionally, the in vivo tumor growth was monitored in the matched PDX models. RESULTS: In vitro PDXO cultures and in vivo PDX tumor models consistently demonstrated that abemaciclib had varying degrees of inhibitory effects across different bladder cancer (BC) patients. Notably, our study further revealed that treatment with abemaciclib significantly modified the expression patterns of CyclinD1/CDK4. This was achieved by not only diminishing their expression levels but also by shifting their expression from a membrane-associated localization to the nucleus. CONCLUSION: Our research provided compelling evidence attesting to the reliability and potential of PDX and PDXO models in the realm of precision medicine. These models are instrumental in identifying patients who are likely to respond favorably to a specific drug treatment.

6.
Ther Adv Med Oncol ; 16: 17588359241286775, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39463748

RESUMO

Background: Abemaciclib was the first cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved globally in the adjuvant setting for high-risk hormone-receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) early breast cancer (EBC), based on the phase III monarchE trial. Objective: To report an exploratory Chinese population analysis based on the preplanned overall survival (OS) interim analysis with 5-year efficacy results of monarchE. Design and methods: Patients with HR+/HER2-, high-risk (⩾4 positive lymph nodes, or 1-3 nodes and either tumor size ⩾5 cm, histologic grade 3, or Ki-67 ⩾20%) EBC were randomized (1:1) to abemaciclib (150 mg twice daily for 2 years) plus endocrine therapy (ET), or ET alone. This analysis included Chinese patients enrolled in mainland China, Hong Kong, and Taiwan. The primary endpoint was invasive disease-free survival (IDFS); key secondary endpoints included distant relapse-free survival (DRFS), safety, and patient-reported outcomes (PROs). Results: Overall, 501 Chinese patients were included (abemaciclib + ET, n = 259; ET, n = 242). With a median follow-up of 53 months, the addition of abemaciclib to ET resulted in improvements in IDFS (estimated 5-year IDFS rate: 85.9% vs 79.1%; hazard ratio (HR), 0.65 (95% confidence interval (CI) 0.41-1.03)) and DRFS (estimated 5-year DRFS rate: 88.4% vs 82.3%; HR, 0.65 (95% CI, 0.39-1.07)). The most common grade ⩾3 treatment-emergent adverse events in the abemaciclib + ET versus ET groups were neutropenia (24.7% vs 0.8%) and leukopenia (22.4% vs 0.4%). Generally, no clinically meaningful difference in PROs (endocrine symptoms and fatigue) was observed between groups, except for diarrhea. Conclusion: At this prespecified OS interim analysis, which provides 5-year data, the addition of abemaciclib to ET in Chinese patients with high-risk HR+, HER2- EBC was associated with sustained and clinically meaningful improvements in IDFS and DRFS, with acceptable safety and tolerability profiles and minimal impact on PROs. These results represent the first full report of a CDK4/6 inhibitor in Chinese patients with EBC and support the positive benefit-risk profile of adjuvant abemaciclib + ET in Chinese patients. Trial registration: ClinicalTrials.gov identifier: NCT03155997 (first posted: May 16, 2017).

7.
J Pharm Biomed Anal ; 253: 116531, 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39454543

RESUMO

An isotope-dilution bioanalytical assay for abemaciclib and its metabolites in combination with olaparib was developed and validated in human plasma K2 EDTA. For the quantitative assay, human plasma samples (or human plasma QC samples) were spiked with internal standard solution before a simple protein precipitation with methanol. The extract was injected onto a liquid chromatography-tandem mass spectrometry (LC-MS/MS) instrument where it was chromatographically separated by a polar end-capped reversed phase column and guard using gradient elution with water and methanol both modified with 0.2 % formic acid (v/v) as the mobile phases. The analytes and internal standards were measured by heated electrospray ionization (HESI) in positive polarity using selected reaction monitoring (SRM) on a triple quadrupole mass spectrometer. The assay was validated for linear ranges as follows: 0.4 - 1000 nM abemaciclib, 0.35 - 1000 nM M2 and M18, 0.5 - 1000 nM M20, and 0.75 - 1000 nM olaparib. The inter-day or between day precision for the quality controls (n = 18) was < 13 % and the accuracy was ± 12 %, for all analytes, including the lower limit of quantification (LLOQ). The intra-day or within day precision for the quality controls (n = 6) was ≤ 11 % and the accuracy was ± 12 % for low, mid, and high and < 19 % at LLOQ. The recovery in human plasma was determined to be between 92 % and 102 % for all analytes spanning the linear range. The validated, bioanalytical quantitative assay was designed to measure abemaciclib, its metabolites, and olaparib for pharmacokinetic evaluation of patients in clinical trials for breast, brain, and ovarian cancers.

8.
Int J Mol Sci ; 25(19)2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39408783

RESUMO

Therapeutic drug monitoring (TDM) may be beneficial for cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), such as palbociclib, ribociclib, and abemaciclib, due to established exposure-toxicity relationships and the potential for monitoring treatment adherence. Developing a method for quantifying CDK4/6is, abemaciclib metabolites (M2, M20), and letrozole in dried blood spots (DBS) could be useful to enhance the feasibility of TDM. Thus, an optimized LC-MS/MS method was developed using the HemaXis DB10 device for volumetric (10 µL) DBS collection. Chromatographic separation was achieved using a reversed-phase XBridge BEH C18 column. Detection was performed with a triple quadrupole mass spectrometer, utilizing ESI source switching between negative and positive ionization modes and multiple reaction monitoring acquisition. Analytical validation followed FDA, EMA, and IATDMCT guidelines, demonstrating high selectivity, adequate sensitivity (LLOQ S/N ≥ 30), and linearity (r ≥ 0.997). Accuracy and precision met acceptance criteria (between-run: accuracy 95-106%, CV ≤ 10.6%). Haematocrit independence was confirmed (22-55%),with high recovery rates (81-93%) and minimal matrix effects (ME 0.9-1.1%). The stability of analytes under home-sampling conditions was also verified. Clinical validation supports DBS-based TDM as feasible, with conversion models developed for estimating plasma concentrations (the reference for TDM target values) of letrozole, abemaciclib, and its metabolites. Preliminary data for palbociclib and ribociclib are also presented.


Assuntos
Aminopiridinas , Benzimidazóis , Teste em Amostras de Sangue Seco , Monitoramento de Medicamentos , Letrozol , Piperazinas , Purinas , Piridinas , Espectrometria de Massas em Tandem , Piperazinas/sangue , Piridinas/sangue , Espectrometria de Massas em Tandem/métodos , Humanos , Monitoramento de Medicamentos/métodos , Purinas/sangue , Letrozol/sangue , Benzimidazóis/sangue , Aminopiridinas/sangue , Teste em Amostras de Sangue Seco/métodos , Cromatografia Líquida/métodos , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/sangue , Espectrometria de Massa com Cromatografia Líquida
9.
BMC Cancer ; 24(1): 1335, 2024 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-39478497

RESUMO

OBJECTIVE: This study explored the predictors of abemaciclib discontinuation, a cyclin-dependent kinase 4 and 6 inhibitor, in patients with breast cancer. MATERIAL AND METHODS: Between November 2018 and March 2023, 147 patients with breast cancer treated with abemaciclib at Osaka Medical and Pharmaceutical University Hospital and Kindai University Nara Hospital were included. The exclusion criteria were as follows: lack of blood testing within 2 weeks prior to starting abemaciclib therapy, transfer to another facility after the commencement of abemaciclib therapy, and discontinuation of abemaciclib therapy due to the diagnosis of another cancer. The duration from the initiation of abemaciclib to discontinuation for any reason and to temporary suspension or dose reduction due to adverse events were analyzed as outcome variables using multivariate Cox regression analysis. RESULTS: Baseline weight < 54 kg, bone metastases, and hemoglobin level ≤ 12.4 g/dL were independent predictors of abemaciclib discontinuation for any reason. The main adverse events leading to abemaciclib discontinuation were liver enzyme elevation and gastrointestinal symptoms. Additionally, focusing on the adverse event of abemaciclib, a baseline weight < 54 kg was an independent predictor of temporary suspension or dose reduction due to adverse events. The most common adverse events leading to temporary suspension or dose reduction were neutropenia and diarrhea. CONCLUSION: Patients with lower body weight are more susceptible to the adverse events of abemaciclib, increasing their risk of treatment discontinuation. In such patients, strict monitoring of adverse events and consideration of more frequent medical visits are necessary from the start of abemaciclib therapy.


Assuntos
Aminopiridinas , Benzimidazóis , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Aminopiridinas/administração & dosagem , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Benzimidazóis/uso terapêutico , Benzimidazóis/efeitos adversos , Benzimidazóis/administração & dosagem , Idoso , Adulto , Suspensão de Tratamento/estatística & dados numéricos , Idoso de 80 Anos ou mais
10.
Cureus ; 16(8): e67714, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39318897

RESUMO

Abemaciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor used for hormone-receptor-positive and human epidermal growth factor receptor 2 (HER-2)-negative breast cancer, can lead to elevated serum creatinine without implications on the true renal function. Although clinical trials have shown no increase in other kidney function biomarkers, this may still represent a challenge in cancer patients. We report a case of a 74-year-old female who presented with creatinine and cystatin-C elevation during treatment with abemaciclib without an equivalent decrease in measured glomerular filtration rate (GFR) with renal scintigraphy. The confirmation of adequate kidney function allowed for the maintenance of treatments that would otherwise be limited by renal impairment. Healthcare providers should be aware of abemaciclib's effect on serum creatinine but should not eliminate the possibility of actual kidney injury. Alternative biomarkers for GFR assessment are recommended, although the usefulness of cystatin-C in patients receiving abemaciclib should be investigated in greater depth.

11.
Cancer Treat Rev ; 130: 102827, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39278067

RESUMO

BACKGROUND: Recently, cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have emerged as a novel treatment strategy for breast cancer. However, increasing reports of CDK4/6i-associated venous thromboembolism (VTE) have garnered attention. This study assessed CDK4/6i-associated VTE in breast cancer, and examined the effect of CDK4/6i on platelet/coagulation function for the first time in vitro. METHODS: PubMed and Embase databases were searched for studies published from the establishment of the database to December 31, 2022 for randomized controlled trials (RCTs) and real-world studies of CDK4/6i in patients with breast cancer, and the data obtained from the included studies were used for meta-analysis. A disproportionality analysis by extracting adverse drug reaction signals of CDK4/6i-associated VTE from the FDA Adverse Event Reporting System (FAERS) database was also conducted. Additionally, the in vitro effect of CDK4/6i on platelet function was assessed based on platelet aggregation tests and flow cytometry, and coagulation function was assessed based on the blood clotting function test. FINDINGS: A total of 16,903 patients in 13 RCTs and 6,490 patients in 9 real-world studies were included in the meta-analysis. In RCTs, VTE occurred in 193 (2.1 %) and 55 (0.7 %) patients in the CDK4/6i and control groups, respectively. In real-world studies, the aggregate incidence rate of VTE was 4.2 % (95 % CI: 2.1, 6.3). The meta-analysis of RCTs revealed that abemaciclib (Odds ratio [OR]: 4.40 [95 % CI: 2.74,7.05], p < 0.001) and palbociclib (OR: 2.35 [95 % CI: 1.34, 4.12], p < 0.01) significantly increased the risk of VTE in patients with breast cancer compared to placebo. FAERS database analysis revealed that abemaciclib (reporting odds ratio [ROR]: 1.63 [95 % CI: 1.36, 1.97]; IC025: 0.67) and ribociclib (ROR: 1.17 [95 % CI: 1.0, 1.39]; IC025: 0.18) demonstrated a significantly increased signal of VTE. Similarly, findings from in vitro experiments demonstrated that abemaciclib enhanced agonist-induced platelet activation, especially when collagen was used as the inducer, and this effect became more prominent with increasing its concentration. INTERPRETATION: Use of abemaciclib may increase the risk of VTE in patients with breast cancer, which may be partially attributed to the effect of abemaciclib on platelet function. Close monitoring of VTE occurrence is highly recommended while using abemaciclib, especially in patients at a high risk of VTE.


Assuntos
Aminopiridinas , Benzimidazóis , Neoplasias da Mama , Farmacovigilância , Tromboembolia Venosa , Humanos , Neoplasias da Mama/tratamento farmacológico , Tromboembolia Venosa/induzido quimicamente , Tromboembolia Venosa/epidemiologia , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Feminino , Aminopiridinas/efeitos adversos , Aminopiridinas/uso terapêutico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Bases de Dados Factuais , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Clin Breast Cancer ; 2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39294027

RESUMO

BACKGROUND: Adjuvant CDK4/6 inhibitors abemaciclib and ribociclib improved disease-free survival (DFS) added to endocrine therapy in hormone receptor (HR)-positive HER2-negative early breast cancer (EBC), in monarchE (NCT03155997) and NATALEE (NCT03701334) trials respectively. We assessed the proportion and outcome of EBC patients qualifying for adjuvant CDK4/6 inhibitors in the real-world. METHODS: Consecutive female patients with HR-positive HER2-negative EBC between 1997 and 2017 from the Australian Capital Territory and South-East New South Wales Breast Cancer Treatment Group registry were analyzed. Patients eligible for abemaciclib had ≥4 axillary nodes involved or 1-3 nodes plus primary >5 cm or grade 3. Ribociclib eligibility was defined as node-positive and node-negative with primary >5 cm or >2 cm grade 3. RESULTS: Of 3840 patients, 671 (17.5%) were abemaciclib-eligible and 1587 (41.3%) ribociclib-eligible . The 5-year DFS was 77% and 94% in abemaciclib-eligible and noneligible registry patients respectively (HR 2.6, 95% CI 2.26-3.05, P < .001). The 5-year DFS was 86% and 97% in ribociclib-eligible and noneligible registry patients respectively (HR 1.92, 95% CI 1.67-2.19, P < .001). Compared with monarchE trial patients, abemaciclib-eligible registry patients were older (median 55 years in registry vs. 51 years in trial), with lower nodal burden (≥4 nodes in 44% in registry vs. 60% in trial). There were more stage III cancers in NATALEE trial patients (60%) than ribociclib-eligible registry patients (24%). CONCLUSIONS: Many women with EBC will qualify for adjuvant CDK4/6 inhibitors (17.5% abemaciclib, 41.3% ribociclib) with resource and workforce implications. In the real-world setting, a greater proportion of adjuvant CDK4/6-eligible patients have lower stage disease, therefore the absolute benefit from treatment may be smaller than estimated by the trials.

13.
Cancers (Basel) ; 16(17)2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39272930

RESUMO

The monarchE study added the CDK4/6 inhibitor abemaciclib to the care of women with oestrogen-positive (ER+) breast cancers. Eligibility required meeting monarchE criteria-either >3 positive axillary nodes, or 1-3 positive sentinel nodes (SNB+) with tumour size >50 mm or grade 3 cancers. Women were advised to proceed to completion axillary node clearance (cANC) if size/grade criteria were not fulfilled for >3 positive nodes to be identified. However, cANC is associated with significant morbidity, conflicting with the potential benefits of abemaciclib. We analysed data of 229 consecutive women (2016-2022) with ER+ breast cancer and SNB+ who proceeded to cANC, keeping with contemporary treatment guidelines. We used this cohort to assess numbers that, under national guidance in place currently, would be advised to undergo cANC solely to check eligibility for abemaciclib treatment. Using monarchE criteria, 90 women (39%) would have accessed abemaciclib based on SNB+ and size/grade, without cANC. In total, 139 women would have been advised to proceed to cANC to check eligibility, with only 15/139 (11%) having >3 positive nodes after sentinel node biopsy and cANC. The remaining 124 (89%) would have undergone cANC but remained ineligible for abemaciclib. Size, age, grade, and Ki67 did not predict >3 nodes at cANC. Following cANC, a large majority of women with ER+, <50 mm, and grade 1-2 tumours remain ineligible for abemaciclib yet are subject to significant morbidity including lifelong lymphoedema risk. The monarchE authors state that 15 women need abemaciclib therapy for 1 to clinically benefit. Thus, in our cohort, 139 women undergoing cANC would lead to one woman benefitting.

14.
Curr Oncol ; 31(9): 5374-5383, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39330025

RESUMO

Endometrial cancer (EC) is a common gynecologic malignancy with a rising incidence due to obesity, comorbid conditions, and related lifestyle factors. The standard of care for primary disease consists of surgical resection with/without chemotherapy ± radiotherapy for select patients. Recurrence is common in patients with advanced-stage disease and/or high-risk features, who primarily are treated with systemic therapy. The identification of novel targets in malignant EC has led to the development of wide-range inhibitors. Abemaciclib is an orally active unique cyclin-dependent kinase (CDK) inhibitor, selective for the CDK4 and CDK6 cell cycle pathways. This agent has potential anti-neoplastic activity and is indicated in combination with various therapies such as endocrine therapy, aromatase inhibitors, and hormone therapies, primarily in breast cancer (BC). Herein, we sought to summarize the biochemical/pharmacological properties of abemaciclib and its therapeutic potential in EC. While the therapeutic role(s) of abemaciclib was fairly established in a subset of patients with advanced/metastatic BC through the pivotal MONARCH trials, its attributes and clinical utility in EC are limited. Thus, based on some promising pre-clinical/translational insights and a recent phase II study, we highlight abemaciclib's properties and potential clinical usefulness in patients with EC, particularly in recurrent estrogen-receptor-positive cases.


Assuntos
Aminopiridinas , Benzimidazóis , Neoplasias do Endométrio , Humanos , Benzimidazóis/uso terapêutico , Benzimidazóis/farmacologia , Feminino , Aminopiridinas/uso terapêutico , Aminopiridinas/farmacologia , Neoplasias do Endométrio/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia
15.
Curr Med Res Opin ; 40(10): 1753-1767, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39305463

RESUMO

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors have emerged as a significant advancement in the treatment of HR+/HER2- metastatic breast cancer (MBC). Despite the clinical efficacy of CDK 4/6 inhibitors in HR+/HER2- metastatic breast cancer, there remains a significant gap in understanding their cost-effectiveness, particularly regarding the long-term economic impact and the key drivers of costs, when used in combination with endocrine therapy. This study aims to systematically review and conduct a meta-analysis of cost-effectiveness studies evaluating CDK4/6 inhibitors in treatment of HR+/HER2- advanced breast cancer and identify key drivers of costs of CDK4/6 inhibitors in combination with endocrine therapy. METHODS: A comprehensive search of PubMed and Embase was conducted to identify peer-reviewed studies from February 2015 to March 2022 reporting cost-effectiveness of CDK4/6 inhibitors in MBC treatment. Incremental net benefits (INBs) were estimated, and meta-analysis was conducted. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: We identified 120 articles, of which 18 were eligible for systematic review and 16 for meta-analysis. None of the three CDK4/6 inhibitors had positive INB compared to endocrine/aromatase inhibitors therapy alone. The pooled INB was estimated at -$149,266.87 (95% Confidence Interval (CI) = -$196,961.54, -$101,572.20). CONCLUSION: The combination of CDK4/6 inhibitors and letrozole/endocrine therapy for the treatment of postmenopausal patients with advanced HR+/HER2 - MBC was not cost-effective.


Breast cancer, a significant health concern worldwide, represents around 30% of new cancer diagnoses and 25% of cancer related fatalities. Among these cases, approximately two-thirds are characterized by hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) tumors. In the metastatic stage, up to half of patients exhibit inherent resistance to endocrine therapy, leading to poorer survival rates, while others, initially responsive, eventually develop resistance, leading to disease progression and eventual mortality. Nevertheless, recent advancements in CDK4/6 inhibitors have shown efficacy in overcoming both inherent and acquired endocrine resistance, representing a substantial breakthrough in HR+/HER2− metastatic breast cancer treatment. This study conducts a review of literature focusing on comparative cost-effectiveness and economic evaluations of the three CDK4/6 inhibitors, evaluating the pooled incremental net benefit (INB) reported in these studies. It marks the first attempt to compare all three CDK4/6 inhibitors and employs a meta-analysis approach to ascertain the option demonstrating the most positive INB. Our findings indicate that CDK4/6 inhibitors fail to provide an economic advantage over letrozole or endocrine therapy alone. The aim of this study is to offer insights for clinical and reimbursement decision-making in the treatment of postmenopausal patients with advanced HR+/HER2− breast cancer, providing valuable guidance for policymakers, payers, and clinicians.


Assuntos
Neoplasias da Mama , Análise de Custo-Efetividade , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Inibidores de Proteínas Quinases , Receptor ErbB-2 , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/economia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Metástase Neoplásica , Piperazinas , Inibidores de Proteínas Quinases/economia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas , Receptor ErbB-2/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-39224861

RESUMO

The most common subtype of breast cancer is hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, accounting for 65-70% of all breast cancer cases diagnosed in the United States. Until 2015, single-agent endocrine therapy (ET) was the recommended first-line treatment for metastatic HR-positive, HER2-negative breast cancer. However, the paradigm has since shifted, as targeted therapy is now recommended in combination with ET. The cyclin-dependent kinase (CDK) 4/6 inhibitors have revolutionized the treatment of this breast cancer subtype, and combining either palbociclib, ribociclib, or abemaciclib with ET is now the standard first-line treatment for metastatic disease. Results of clinical trials in the metastatic setting have demonstrated that treatment with the combination of a CDK4/6 inhibitor and ET rather than ET alone is associated with longer overall survival, longer progression-free survival, and better objective response rates. Each of the CDK4/6 inhibitors has been investigated in combination with ET in patients with early-stage HR-positive, HER2-negative breast cancer who are at high risk of relapse. In October 2021, abemaciclib was the first CDK4/6 inhibitor approved in combination with ET by the US Food and Drug Administration for adjuvant treatment of patients with HR-positive, HER2-negative, high-risk early breast cancer. Herein, we provide practical guidance on the use of abemaciclib in combination with ET for HR-positive, HER2-negative, high-risk early breast cancer to assist clinicians in their day-to-day practice, and we review clinically relevant topics of dosing, side effect management, sequencing and optimal timing for initiation, and patient selection.

17.
Breast Cancer Res Treat ; 207(3): 529-532, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39110275

RESUMO

PURPOSE: Approximately 15% of women who receive ovarian function suppression (OFS) as adjuvant treatment for high-risk, localized hormone receptor-positive (HR+) breast cancer may have inadequate estradiol suppression which can require therapeutic modification when used in combination with an aromatase inhibitor (AI). We previously reported that abemaciclib may interfere with the estradiol Abbott Alinity chemiluminescent microparticle immunoassay (CMIA) commonly used to monitor estradiol levels and suggested liquid chromatography-mass spectrometry (LC-MS/MS) is preferred in this setting. The aim of this study was to determine discrepancies in estradiol levels using CMIA compared to LC-MS/MS and subsequent treatment changes in a larger patient population. METHODS: We conducted a retrospective review of premenopausal women with early-stage HR+ breast cancer at our institution who received adjuvant OFS and abemaciclib with at least 1 CMIA estradiol level drawn during abemaciclib therapy from October 2021 to April 2023. RESULTS: Of the 22 women who met criteria for review, 20 (90.9%) had CMIA estradiol levels in the premenopausal range, of whom 9 also had estradiol measured by LC-MS/MS. All 9 women receiving OFS and abemaciclib with estradiol measurements by both methods had premenopausal range CMIA estradiol levels and postmenopausal range LC-MS/MS estradiol levels. Of the 20 patients with premenopausal estradiol levels by CMIA estradiol, treatment changes included increased OFS dosage or preparation (n = 7), change from AI to tamoxifen (n = 3), and surgical oophorectomy (n = 7). CONCLUSION: Our findings suggest the likely interference of abemaciclib with the Abbott Alinity immunoassay which may lead to unnecessary treatment changes. It is recommended that the LC-MS/MS assay be used when monitoring estradiol levels in patients receiving abemaciclib concurrently with OFS.


Assuntos
Benzimidazóis , Neoplasias da Mama , Estradiol , Pré-Menopausa , Humanos , Feminino , Estradiol/sangue , Neoplasias da Mama/tratamento farmacológico , Adulto , Estudos Retrospectivos , Benzimidazóis/uso terapêutico , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem , Aminopiridinas/uso terapêutico , Cromatografia Líquida , Inibidores da Aromatase/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Quimioterapia Adjuvante/métodos , Ovário/efeitos dos fármacos , Ovário/metabolismo
18.
Cancers (Basel) ; 16(15)2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39123441

RESUMO

The current 5-year survival rate of pancreatic cancer is about 12%, making it one of the deadliest malignancies. The rapid metastasis, acquired drug resistance, and poor patient prognosis necessitate better therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC). Multiple studies show that combining chemotherapeutics for solid tumors has been successful. Targeting two distinct emerging hallmarks, such as non-mutational epigenetic changes by panobinostat (Pan) and delayed cell cycle progression by abemaciclib (Abe), inhibits pancreatic cancer growth. HDAC and CDK4/6 inhibitors are effective but are prone to drug resistance and failure as single agents. Therefore, we hypothesized that combining Abe and Pan could synergistically and lethally affect PDAC survival and proliferation. Multiple cell-based assays, enzymatic activity experiments, and flow cytometry experiments were performed to determine the effects of Abe, Pan, and their combination on PDAC cells and human dermal fibroblasts. Western blotting was used to determine the expression of cell cycle, epigenetic, and apoptosis markers. The Abe-Pan combination exhibited excellent efficacy and produced synergistic effects, altering the expression of cell cycle proteins and epigenetic markers. Pan, alone and in combination with Abe, caused apoptosis in pancreatic cancer cells. Abe-Pan co-treatment showed relative safety in normal human dermal fibroblasts. Our novel combination treatment of Abe and Pan shows synergistic effects on PDAC cells. The combination induces apoptosis, shows relative safety, and merits further investigation due to its therapeutic potential in the treatment of PDAC.

19.
BMC Pharmacol Toxicol ; 25(1): 47, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39123221

RESUMO

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors marked a milestone in the breast cancer treatment. Due to the potential impact of adverse effects on treatment decisions and patient outcomes, careful consideration of the varying toxicities of CDK4/6 inhibitors is crucial, as three inhibitors-palbociclib, abemaciclib, and ribociclib-have been approved with differences in adverse event profiles. However, limitations in clinical trials call for urgent real-world safety studies to evaluate and compare the risk of adverse events (AEs) among these CDK4/6 inhibitors. Therefore, this study aimed to analyze AEs of CDK4/6 inhibitors and provide insights for clinical drug selection, using real world database. METHODS: The AEs of CDK4/6 inhibitors in the FDA Adverse Event Reporting System (2015-2022) were analyzed. Four disproportionality methods were used to detect safety signals: reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Neural Network Propagation, and Multi-Item Gamma Poisson Shrinker. Venn analysis was used to compare and select common and specific AEs. RESULTS: This study included 73,042 patients treated with palbociclib, 25,142 with ribociclib, and 7563 with abemaciclib. All three inhibitors had 27 common AEs. Palbociclib exhibited the highest ROR for hematologic toxicities, while ribociclib showed the highest ROR for macrocytosis, nail disorders, and hepatic lesions. Abemaciclib displayed the highest ROR for mucosal toxicity. Common signals for both palbociclib and ribociclib included hematologic toxicities, decreased immune responsiveness, and aphthous ulcers. Myelosuppression, oral pain, and pseudocirrhosis were common signals for palbociclib and abemaciclib. Anemia, hepatotoxicity, and pneumonitis were observed as common signals for ribociclib and abemaciclib. Furthermore, specific AEs associated with palbociclib included fatigue, alopecia, and stomatitis. For ribociclib, specific AEs included electrocardiogram QT prolongation, thrombocytopenia, and decreased hemoglobin. Abemaciclib was specifically linked to diarrhea, vomiting, and interstitial lung disease. CONCLUSION: Our analysis revealed that palbociclib showed a higher risk of hematologic toxicity. Ribociclib showed higher risks of hepatotoxicity, nephrotoxicity, and QT prolongation. Abemaciclib showed higher risks of hepatotoxicity, gastrointestinal effects, interstitial lung disease, and thrombosis. These findings provide valuable insights for CDK4/6 inhibitor selection.


Assuntos
Aminopiridinas , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Piperazinas , Inibidores de Proteínas Quinases , Purinas , Piridinas , Feminino , Humanos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Aminopiridinas/efeitos adversos , Antineoplásicos/efeitos adversos , Benzimidazóis/efeitos adversos , Estudos de Casos e Controles , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Farmacovigilância , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/efeitos adversos , Piridinas/efeitos adversos , Estados Unidos/epidemiologia , United States Food and Drug Administration
20.
Cancers (Basel) ; 16(16)2024 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-39199640

RESUMO

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are approved for the treatment of human epidermal growth factor receptor 2 (HER-2)-negative, hormone receptor-positive breast cancer. The cardiovascular toxicity of CDK4/6 inhibitors is not well understood. This study aims to profile the cardiac events associated with CDK4/6 inhibitors. Reports from 2015Q1 to 2024Q1 were obtained from the FDA Adverse Event Reporting System (FAERS). Reports identifying palbociclib, ribociclib, and abemaciclib as the primary suspect were examined for cardiovascular toxicity, including hypertension, cardiac failure, cardiomyopathy, arrhythmia, myocardial infarction, and myocarditis. Signal detection was performed using the proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC). A total of 69,139 reports were analyzed. The median time to adverse events was 69 days (interquartile range [IQR], 18-260 days). Of these, 2065 reports documented cardiac adverse events. Ribociclib and QT prolongation were re-confirmed as a signal (PRR 8.43, ROR 8.65, IC025 2.86). Hypertension and cardiac failure were the most frequently reported cardiovascular toxicities. This study demonstrates that the use of CDK4/6 inhibitors is associated with cardiovascular adverse events, such as heart failure and hypertension. Further research is needed to understand the mechanisms and risk factors contributing to the cardiovascular toxicity of CDK4/6 inhibitors.

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