RESUMO
The serine/threonine kinase PAK4 plays a crucial role in regulating cell proliferation, survival, migration, and invasion. Overexpression of PAK4 correlates with poor prognosis in some cancers. KPT-9274, a PAK4 inhibitor, significantly reduces the growth of triple-negative breast cancer cells and mammary tumors in mouse models, and it also inhibits the growth of several other types of cancer cells. Interestingly, although it was first identified as a PAK4 inhibitor, KPT-9274 was also found to inhibit the enzyme NAMPT (nicotinamide phosphoribosyltransferase), which is crucial for NAD (nicotinamide adenine dinucleotide) synthesis and vital for cellular energy and growth. These results made us question whether growth inhibition in response to KPT-9274 was due to PAK4 inhibition, NAMPT inhibition, or both. To address this, we tested several other PAK4 inhibitors that also inhibit cell growth, to determine whether they also inhibit NAMPT activity. Our findings confirm that multiple PAK4 inhibitors also inhibit NAMPT activity. This was assessed both in cell-free assays and in a breast cancer cell line. Molecular docking studies were also used to help us better understand the mechanism by which PAK4 inhibitors block PAK4 and NAMPT activity, and we identified specific residues on the PAK4 inhibitors that interact with NAMPT and PAK4. Our results suggest that PAK4 inhibitors may have a more complex mechanism of action than previously understood, necessitating further exploration of how they influence cancer cell growth.
Assuntos
Citocinas , Simulação de Acoplamento Molecular , Nicotinamida Fosforribosiltransferase , Quinases Ativadas por p21 , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/metabolismo , Quinases Ativadas por p21/antagonistas & inibidores , Quinases Ativadas por p21/metabolismo , Humanos , Linhagem Celular Tumoral , Citocinas/metabolismo , Proliferação de Células/efeitos dos fármacos , Acrilamidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Feminino , Benzenoacetamidas/farmacologia , AminopiridinasRESUMO
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/farmacologiaRESUMO
Musculoskeletal traumatic injuries (MTI) involve soft tissue lesions adjacent to a bone fracture leading to fibrous nonunion. The impact of MTI on the inflammatory response to fracture and on the immunomodulation of skeletal stem/progenitor cells (SSPCs) remains unknown. Here, we used single-nucleus transcriptomic analyses to describe the immune cell dynamics after bone fracture and identified distinct macrophage subsets with successive pro-inflammatory, pro-repair and anti-inflammatory profiles. Concurrently, SSPCs transition via a pro- and anti-inflammatory fibrogenic phase of differentiation prior to osteochondrogenic differentiation. In a preclinical MTI mouse model, the injury response of immune cells and SSPCs is disrupted leading to a prolonged pro-inflammatory phase and delayed resolution of inflammation. Macrophage depletion improves bone regeneration in MTI demonstrating macrophage involvement in fibrous nonunion. Finally, pharmacological inhibition of macrophages using the CSF1R inhibitor Pexidartinib ameliorates healing. These findings reveal the coordinated immune response of macrophages and skeletal stem/progenitor cells as a driver of bone healing and as a primary target for the treatment of trauma-associated fibrosis.
Assuntos
Macrófagos , Animais , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Regeneração Óssea/efeitos dos fármacos , Masculino , Fraturas Ósseas/imunologia , Fraturas Ósseas/patologia , Diferenciação Celular/efeitos dos fármacos , Pirróis/farmacologia , Pirróis/uso terapêutico , Consolidação da Fratura/efeitos dos fármacos , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Sistema Musculoesquelético/lesõesRESUMO
AIM: Assessment of CBR, PFS, QOL and toxicity profile of palbociclib and ribociclib. METHODS: This is an interventional concurrent randomised phase III open label clinical trial. It took place at the Oncology Centre Mansoura University, Egypt from July 2022 till December 2023. Patients with pathologically proved ER+ HER2- metastatic breast cancer who either progressed on adjuvant hormonal or progressed on 1st line hormonal for metastatic disease. Patients in arm A received palbociclib 125 mg/day orally for 3 weeks and 1 week rest, plus fulvestrant. Patients in Arm B received ribociclib at a dose of 600 mg, administered orally once daily for 3 weeks and 1 week rest, plus fulvestrant. Pre- and peri-menopausal women received the LHRH agonist goserelin. Patients who lost their endorsement and were considered to be lost to follow up. Quality of life was analysed using the (EORTC) quality-of-life questionnaire (QLQ)-C30 V3.0. Patients were asked to complete the questionnaires at screening; at the 2nd and 6th month. Toxicity was assessed and graded using (CTCAE) v5.0. Patients were evaluated clinically for response and toxicity monthly and radiologically by CT and tumor markers/ 3 months. Treatment continued until objective Progressive Disease (PD), symptomatic deterioration, unacceptable toxicity or death. RESULTS: Both arms had similar baseline characteristics. There was no statistically significant difference regarding the CBR (58.6% for both arms at 6 months and 13.8% in the palbociclib VS 17.2% in the ribociclib arm at 12 months). The median PFS to the whole population was 13 months. COX multivariate analysis revealed that postmenopausal had 2.85 more likely to survive than premenopausal patients. Patients with ECOG performance status 2 and 3 are 0.13 and 0.39 less likely to survive compared to patients with PS 1. Dose reduction increased the likelihood of survival 3.36 compared with no dose reduction. The median PFS was 13.67 months in the palbociclib arm and 12.69 months in the ribociclib arm with no statistically significant difference. During follow up, there was statistically significant improvement in insomnia in both arms and constipation in the palbociclib arm alone. Comparing the two arms, no statistically significant deterioration in the QOL domains except in fatigue and financial difficulties, with more deterioration in the palbociclib arm. Regarding common toxicities there was no statistically significant difference between the 2 arms. CONCLUSIONS: Both Ribociclib and palbociclib have similar CBR, PFS and toxicity profile.
Assuntos
Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Fulvestranto , Piperazinas , Purinas , Piridinas , Qualidade de Vida , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Aminopiridinas/administração & dosagem , Piridinas/administração & dosagem , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Purinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , Fulvestranto/administração & dosagem , Adulto , Seguimentos , Prognóstico , Taxa de SobrevidaRESUMO
The combination of ASC22, an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide, a HIV latency reversal agent, may serve as a strategy for antiretroviral therapy-free virological control for HIV. People living with HIV, having achieved virological suppression, were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy. Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8+ T cells (NCT05129189). 15 participants completed the study. At week 8, CA HIV RNA levels showed a significant increase from baseline, and the values returned to baseline after discontinuing ASC22 and chidamide. The total HIV DNA was only transiently increased at week 4 (P = 0.014). In contrast, integrated HIV DNA did not significantly differ from baseline. Increases in the proportions of effector memory CD4+ and CD8+ T cells (TEM) were observed from baseline to week 24 (P = 0.034 and P = 0.002, respectively). The combination treatment did not succeed in enhancing the function of HIV Gag/Pol- specific CD8+ T cells. Nevertheless, at week 8, a negative correlation was identified between the proportions of HIV Gag-specific TEM cells and alterations in integrated DNA in the T cell function improved group (P = 0.042 and P = 0.034, respectively). Nine adverse events were solicited, all of which were graded 1 and resolved spontaneously. The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs. Further investigations are warranted in the context of analytic treatment interruption.
Assuntos
Aminopiridinas , Benzamidas , Linfócitos T CD8-Positivos , Infecções por HIV , HIV-1 , Inibidores de Histona Desacetilases , Humanos , Masculino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Infecções por HIV/imunologia , Infecções por HIV/genética , Aminopiridinas/farmacologia , Feminino , Adulto , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Benzamidas/administração & dosagem , Pessoa de Meia-Idade , HIV-1/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Antígeno B7-H1/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Latência Viral/efeitos dos fármacos , Carga Viral/efeitos dos fármacosRESUMO
Background: Angioimmunoblastic T-cell lymphoma (AITL) is known for its unfavorable survival prognosis. Chidamide has shown efficacy in relapsed/refractory AITL, but its efficacy in newly diagnosed AITL is uncertain. Objective: This retrospective research aimed to evaluate the effectiveness and safety of chidamide when used with doxorubicin, cyclophosphamide, prednisone, and vincristine (CHOP) in comparison to CHOP by itself for individuals newly diagnosed with AITL, and to examine the impact of transplantation. Method: This was an analysis that compared outcomes among patients who received chidamide + CHOP on a clinical trial vs. historical controls who received CHOP alone, enrolling a total of sixty-six treatment-naive AITL patients between April 2014 and November 2022. Among them, thirty-three received chidamide in addition to CHOP (chidamide group), while thirty-three received CHOP alone (control group). The clinical characteristics were balanced between the two groups. All patients were scheduled to undergo up to six courses of treatment before transplantation. Results: The chidamide group had a significantly longer median overall survival (OS) compared to the control group, with a median OS that was not reached, as opposed to 20 months in the control group (p = 0.002). In the control group, the median progression-free survival (PFS) was 11 months, while in the chidamide group, it was 22 months (p = 0.080). In the high-risk group (IPI ≥ 3), the chidamide group demonstrated notably superior complete response (CR) and overall response rate (ORR) compared to the control cohort (p = 0.002, p = 0.034). The PFS and OS in the chidamide group were not reached, and there were significant differences compared to the control group (p = 0.007, p = 0.003). The median OS of the transplanted group was longer than the non-transplanted group (p = 0.004). On multivariate analysis, chidamide group reduced the hazards of death in the total cohort. Conclusion: As the study was non-random and retrospective, Chidamide combined with chemotherapy should be tested in randomized trials given its potential to improve prognosis in treatment-naive AITL patients. Furthermore, autologous hematopoietic stem cell transplantation (auto-HSCT) has demonstrated enhanced overall survival in individuals with AITL. Clinical trial registration: https://clinicaltrials.gov/, NCT03268889.
Assuntos
Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aminopiridinas/uso terapêutico , Aminopiridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/uso terapêutico , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Doxorrubicina/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Linfoma de Células T/mortalidade , Linfoma de Células T/terapia , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/diagnóstico , Prednisona/uso terapêutico , Prednisona/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento , Vincristina/uso terapêutico , Vincristina/administração & dosagemAssuntos
Aminopiridinas , Benzamidas , Ciclopropanos , Dermatite Atópica , Inibidores da Fosfodiesterase 4 , Humanos , Dermatite Atópica/tratamento farmacológico , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Aminopiridinas/administração & dosagem , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/efeitos adversos , Inibidores da Fosfodiesterase 4/administração & dosagem , Ciclopropanos/uso terapêutico , Ciclopropanos/efeitos adversos , Ciclopropanos/administração & dosagem , Ciclopropanos/farmacologia , Ciclopropanos/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/uso terapêutico , Creme para a Pele/administração & dosagem , Administração CutâneaRESUMO
Patients with anaplastic lymphoma kinase (ALK)-driven neuroblastoma may respond to tyrosine kinase inhibitors, but resistance to treatment occurs and methods currently used for detection of residual disease have limited sensitivity. Here, we present a national unselected cohort of five patients with relapsed or refractory ALK-driven neuroblastoma treated with lorlatinib as monotherapy and test the potential of targeted circulating tumor DNA (ctDNA) analysis as a guide for treatment decisions in these patients. We developed a sequencing panel for ultrasensitive detection of ALK mutations associated with neuroblastoma or resistance to tyrosine kinase inhibitors and used it for ctDNA analysis in 83 plasma samples collected longitudinally from the four patients who harbored somatic ALK mutations. All four patients with ALK p.R1275Q experienced major responses and were alive 35 to 61 months after starting lorlatinib. A fifth patient with ALK p.F1174L initially had a partial response but relapsed after 10 months of treatment. In all cases, ctDNA was detected at the start of lorlatinib single-agent treatment and declined gradually, correlating with clinical responses. In the two patients exhibiting relapse, ctDNA increased 9 and 3 months, respectively, before clinical detection of disease progression. In one patient harboring HRAS p.Q61L in the relapsed tumor, retrospective ctDNA analysis showed that the mutation appeared de novo after 8 months of lorlatinib treatment. We conclude that some patients with relapsed or refractory high-risk neuroblastoma show durable responses to lorlatinib as monotherapy, and targeted ctDNA analysis is effective for evaluation of treatment and early detection of relapse in ALK-driven neuroblastoma. SIGNIFICANCE: We present five patients with ALK-driven relapsed or refractory neuroblastoma treated with lorlatinib as monotherapy. All patients responded to treatment, and four of them were alive after 3 to 5 years of follow-up. We performed longitudinal ctDNA analysis with ultra-deep sequencing of the ALK tyrosine kinase domain. We conclude that ctDNA analysis may guide treatment decisions in ALK-driven neuroblastoma, also when the disease is undetectable using standard clinical methods.
Assuntos
Aminopiridinas , Quinase do Linfoma Anaplásico , DNA Tumoral Circulante , Lactamas Macrocíclicas , Lactamas , Neuroblastoma , Pirazóis , Humanos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/sangue , Neuroblastoma/genética , Quinase do Linfoma Anaplásico/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Aminopiridinas/uso terapêutico , Feminino , Lactamas Macrocíclicas/uso terapêutico , Masculino , Pirazóis/uso terapêutico , Pré-Escolar , Resistencia a Medicamentos Antineoplásicos/genética , Criança , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/sangue , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Lactente , Resultado do TratamentoRESUMO
Reactions with allyl-, acetyl-, and phenylisothiocyanate have been studied on the basis of 3-amino-4,6-dimethylpyridine-2(1H)-one, 3-amino-4-phenylpyridine-2-one, and 3-amino-4-(thiophene-2-yl)pyridine-2(1H)-one (benzoyl-)isothiocyanates, and the corresponding thioureide derivatives 8-11a-c were obtained. Twelve thiourea derivatives were obtained and studied for their anti-diabetic activity against the enzyme α-glucosidase in comparison with the standard drug acarbose. The comparison drug acarbose inhibits the activity of α-glucosidase at a concentration of 15 mM by 46.1% (IC50 for acarbose is 11.96 mM). According to the results of the conducted studies, it was shown that alkyl and phenyl thiourea derivatives 8,9a-c, in contrast to their acetyl-(benzoyl) derivatives and 10,11a-c, show high antidiabetic activity. Thus, 1-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-3-phenylthiourea 9a has the highest inhibitory activity against the enzyme α-glucosidase, exceeding the activity of the comparison drug acarbose, which inhibits the activity of α-glucosidase by 56.6% at a concentration of 15 mm (IC50 = 9,77 mM). 1-(6-methyl-2-oxo 4-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)-3-phenylthiourea 9c has inhibitory activity against the enzyme α-glucosidase, comparable to the comparison drug acarbose, inhibiting the activity of α-glucosidase at a concentration of 15 mm per 41.2% (IC50 = 12,94 mM). Compounds 8a, 8b, and 9b showed inhibitory activity against the enzyme α-glucosidase, with a lower activity compared to acarbose, inhibiting the activity of α-glucosidase at a concentration of 15 mM by 23.3%, 26.9%, and 35.2%, respectively. The IC50 against α-glucosidase for compounds 8a, 8b, and 9b was found to be 16.64 mM, 19.79 mM, and 21.79 mM, respectively. The other compounds 8c, 10a, 10b, 10c, 11a, 11b, and 11c did not show inhibitory activity against α-glucosidase. Thus, the newly synthesized derivatives of thiourea based on 3-aminopyridine-2(1H)-ones are promising candidates for the further modification and study of their potential anti-diabetic activity. These positive bioanalytical results will stimulate further in-depth studies, including in vivo models.
Assuntos
Inibidores de Glicosídeo Hidrolases , Tioureia , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/síntese química , Tioureia/química , Tioureia/farmacologia , Tioureia/análogos & derivados , Tioureia/síntese química , alfa-Glucosidases/metabolismo , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Estrutura Molecular , Aminopiridinas/química , Aminopiridinas/farmacologia , Aminopiridinas/síntese químicaRESUMO
Microglia, traditionally regarded as innate immune cells in the brain, drive neuroinflammation and synaptic dysfunctions in the early phases of Alzheimer disease (AD), acting upstream to Aß accumulation. Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its levels are significantly increased in neurodegenerative diseases, possibly contributing to the chronic inflammatory microglial response. On the other hand, CSF-1R inhibitors confer neuroprotection in preclinical models of neurodegenerative diseases. Here, we determined the effects of the CSF-1R inhibitor PLX3397 on the Aß-mediated synaptic alterations in ex vivo hippocampal slices. Electrophysiological findings show that PLX3397 rescues LTP impairment and neurotransmission changes induced by Aß. In addition, using confocal imaging experiments, we demonstrate that PLX3397 stimulates a microglial transition toward a phagocytic phenotype, which in turn promotes the clearance of Aß from glutamatergic terminals. We believe that the selective pruning of Aß-loaded synaptic terminals might contribute to the restoration of LTP and excitatory transmission alterations observed upon acute PLX3397 treatment. This result is in accordance with the mechanism proposed for CSF1R inhibitors, that is to eliminate responsive microglia and replace it with newly generated, homeostatic microglia, capable of promoting brain repair. Overall, our findings identify a connection between the rapid microglia adjustments and the early synaptic alterations observed in AD, possibly highlighting a novel disease-modifying target.
Assuntos
Aminopiridinas , Peptídeos beta-Amiloides , Hipocampo , Potenciação de Longa Duração , Microglia , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Peptídeos beta-Amiloides/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Aminopiridinas/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Pirróis/farmacologia , Camundongos , Fagocitose/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Ácido Glutâmico/metabolismoRESUMO
BACKGROUND: Chronic inflammatory skin diseases are of great social and medical importance and require effective drug therapy. Phosphodiesterase 4 (PDE4) inhibitors represent a possible therapeutic option by regulating inflammatory processes. PDEs cause the release of proinflammatory cytokines by interfering with signaling pathways. The PDE4 inhibitors apremilast (treatment of psoriasis and Behçet's disease), roflumilast (treatment of chronic obstructive pulmonary disease), and crisaborole (treatment of atopic dermatitis) are currently approved in Europe. PSORIASIS: Apremilast is used for second-line treatment of plaque psoriasis and psoriatic arthritis and has a favorable side effect profile. Topical PDE4 inhibitors are currently being researched and have not yet been approved by the European Medicines Agency (EMA). ATOPIC DERMATITIS: The topical PDE4 inhibitor crisaborole was approved by the EMA in 2020 as a topical treatment alternative to glucocorticoids and calcineurin inhibitors. Although the substance has shown good tolerability in studies and also alleviates the accompanying itching, it did not find its way onto the German market. BEHçET'S DISEASE: Apremilast is approved for the treatment of Behçet's disease in adults with refractory, severe oral ulcers. OUTLOOK: Case studies have also demonstrated the efficacy of systemic PDE4 inhibition in other skin diseases (including blistering autoimmune dermatoses, lichen planus, and acantholytic genodermatoses). The substances are also being researched and used to treat extracutaneous inflammatory diseases.
Assuntos
Inibidores da Fosfodiesterase 4 , Psoríase , Talidomida , Humanos , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/efeitos adversos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Talidomida/farmacologia , Talidomida/efeitos adversos , Psoríase/tratamento farmacológico , Dermatopatias/tratamento farmacológico , Benzamidas/uso terapêutico , Benzamidas/farmacologia , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Compostos de Boro/uso terapêutico , Compostos de Boro/farmacologia , Síndrome de Behçet/tratamento farmacológico , Dermatite Atópica/tratamento farmacológico , Ciclopropanos , Compostos Bicíclicos Heterocíclicos com PontesRESUMO
BACKGROUND: In the last decade, a fundamental shift in the treatment of cystic fibrosis (CF) took place due to the introduction of CF transmembrane conductance regulator (CFTR) modulators. Adequate medication adherence is a prerequisite for their effectiveness, but little is known about adherence to CFTR modulators. We aimed to assess the extent of medication adherence to CFTR modulators in patients with CF and assess which characteristics are associated with adherence. METHODS: A systematic review following PRISMA guidelines was performed. Studies needed to report adherence to CFTR modulators. Main outcomes were: 1) level of medication adherence and 2) associations of demographic and/or clinical characteristics with adherence. RESULTS: In total, 4082 articles were screened and 21 full-text papers were assessed for eligibility. Ultimately, seven studies were included. Most studies were retrospective and focused on adherence to ivacaftor or lumacaftor-ivacaftor with only one focusing on elexacaftor-tezacaftor-ivacaftor. The majority used pharmacy refill data with adherence determined with the proportion of days covered (PDC) or the medication possession ratio (MPR). One study additionally used electronic monitoring and patient self-reported adherence. Adherence was 0.62-0.99 based on pharmacy data (PDC or MPR), 61% via electronic monitoring and 100% via self-report. Age <18â years appeared to be associated with good adherence, as was a higher lung function. CONCLUSIONS: Despite the wide variety of adherence methods used, adherence to CFTR modulators is suboptimal, based on objective measures such as pharmacy refill data or electronic monitoring. CFTR modulator adherence measurement and definitions requires more standardisation with a preference for objective and granular methods.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Adesão à Medicação , Fibrose Cística/tratamento farmacológico , Fibrose Cística/fisiopatologia , Humanos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Resultado do Tratamento , Agonistas dos Canais de Cloreto/uso terapêutico , Quinolonas/uso terapêutico , Feminino , Masculino , Adolescente , Adulto Jovem , Combinação de Medicamentos , Adulto , Criança , Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Pré-Escolar , BenzodioxóisRESUMO
PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have demonstrated significant clinical benefits in progression-free and overall survival. This study investigates the outcomes associated with two kinds of CDK4/6i in patients with hormone receptor (HR)-positive metastatic and relapsed breast cancer to inform real-world evidence of treatment strategies. METHODS: This retrospective study included 340 Taiwanese patients with HR-positive advanced breast cancer from the Taipei Veterans General Hospital, between 2018 and 2023. We analyzed patient characteristics, treatment strategies and outcomes associated with two CDK4/6i. The efficacy of patients who experienced economic burden and interrupted CDK4/6i treatment after 2 years of National Health Insurance (NHI) reimbursement was also investigated. RESULTS: Patients receiving ribociclib and palbociclib showed no significant differences in age, histology, body mass index(BMI), or pathologic status. The distribution of disease status and endocrine therapy partners was comparable between the two groups. Dose reduction was similar, while patients with palbociclib tended to discontinue CDK4/6i usage, and those with ribociclib tended to switch to the other CDK4/6i or endocrine partners. There was no significant difference in progression-free survival (PFS) between the two CDK4/6i in the first-line setting. Adverse prognostic factors were increasing HER2 IHC score, higher Ki-67 levels, visceral and liver metastasis, prior chemotherapy, and endocrine therapy resistance, while higher BMI, bone-only metastasis, and letrozole treatment were associated with a lower risk of progression. The limited follow-up time in our study was insufficient to assess the outcomes of patients treated with interrupted CDK4/6i for up to two years under the NHI reimbursement policy. CONCLUSION: Treatment outcomes between the two types of CDK4/6i did not differ significantly, indicating the safety and efficacy of CDK4/6i for the Asian population. Ribociclib and palbociclib showed similar efficacy in PFS in the real-world setting.
Assuntos
Aminopiridinas , Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Piperazinas , Inibidores de Proteínas Quinases , Purinas , Piridinas , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Pessoa de Meia-Idade , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Piridinas/uso terapêutico , Estudos Retrospectivos , Idoso , Piperazinas/uso terapêutico , Aminopiridinas/uso terapêutico , Purinas/uso terapêutico , Taiwan , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Resultado do Tratamento , Metástase Neoplásica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Povo AsiáticoRESUMO
BACKGROUND: The current standard first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR + /HER2 -) advanced breast cancer (ABC) is a combination of aromatase inhibitor (AI) plus CDK4/6 inhibitors (CDK4/6i). Direct comparison trials of different CDK4/6i are scarce. This real-world study compared the effectiveness of first-line AI plus ribociclib versus palbociclib. METHODS: This multicenter retrospective cohort study, conducted in six cancer centers in Thailand, enrolled patients with HR + /HER2 - ABC treated with first-line AI, and either ribociclib or palbociclib. Propensity score matching (PSM) was performed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), time to chemotherapy (TTC), and adverse events. RESULTS: Of the 250 patients enrolled, 134 patients with ribociclib and 49 patients with palbociclib were captured after PSM. Baseline characteristics were well-balanced between groups. Median PFS in patients receiving ribociclib and palbociclib were 27.9 and 31.8 months, respectively (hazard ratio: 0.87; 0.55-1.37). The median OS in the AI + ribociclib arm was 48.7 months compared to 59.1 months in the AI + palbociclib arm (hazard ratio: 0.55; 0.29-1.05). The median TTC in the AI + palbociclib group was 56 months, but not reached in the AI + ribociclib group (p = 0.42). The ORR of AI + ribociclib and AI + palbociclib were comparable (40.5% vs. 53.6%, p = 0.29). Patients receiving palbociclib demonstrated a higher proportion of neutropenia compared to those receiving ribociclib, despite a similar dose reduction rate (p = 0.28). Hepatitis rate was similar between the ribociclib (21%) and palbociclib groups (22%). Additionally, a low incidence of QT prolongation was observed in both the ribociclib (5%) and palbociclib groups (4%). CONCLUSION: This preliminary analysis of a real-world study demonstrated the comparable effectiveness of ribociclib and palbociclib with AI as an initial therapy for HR + /HER2 - ABC. No statistically significant difference in PFS, OS, and TTC was found in patients treated with AI combined with palbociclib or ribociclib. Longer follow-up and further prospective randomized head-to-head studies are warranted.
Assuntos
Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Piperazinas , Purinas , Piridinas , Receptor ErbB-2 , Receptores de Estrogênio , Humanos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Feminino , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Aminopiridinas/administração & dosagem , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Purinas/administração & dosagem , Purinas/efeitos adversos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos Retrospectivos , Tailândia/epidemiologia , Idoso , Receptor ErbB-2/metabolismo , Adulto , Receptores de Estrogênio/metabolismo , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/uso terapêutico , Receptores de Progesterona/metabolismo , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: The MONALEESA7 and 2 phase 3 randomized trials demonstrated a statistically significant progressionfree survival (PFS) and overall survival (OS) benefit with initial ribociclib + endocrine therapy (ET) versus placebo + ET in pre and postmenopausal patients with hormone receptorpositive (HR+)/human epidermal growth factor receptor 2negative (HER2−) advanced breast cancer (ABC), respectively. Similar trends were observed in Asian subgroup analyses. This phase 2 bridging study of initial ET + ribociclib enrolled pre and postmenopausal patients with HR+/HER2 ABC from China and was conducted to demonstrate consistency of PFS results in a Chinese population relative to the global MONALEESA7 and 2 studies. METHODS: Patients were randomized (1:1) to ET (nonsteroidal aromatase inhibitor + goserelin for premenopausal patients; letrozole for postmenopausal patients) + either ribociclib or placebo. The primary endpoint was investigatorassessed PFS. RESULTS: As of April 25, 2022, the median followup was 34.7 months in both cohorts. In the premenopausal cohort, median PFS was 27.6 months in the ribociclib arm (n = 79) versus 14.7 months in the placebo arm (n = 77) (hazard ratio 0.67 [95% CI: 0.45, 1.01]). In the postmenopausal cohort, median PFS was not reached in the ribociclib arm versus 18.5 months in the placebo arm (n = 77 in each arm) (hazard ratio 0.40 [95% CI: 0.26, 0.62]). Data also suggested improvements in secondary efficacy endpoints, although OS data were not mature. The safety profile in this population was consistent with that in global studies. CONCLUSIONS: These data demonstrate a favorable benefitrisk profile for ribociclib + ET in Chinese patients.
Assuntos
Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Letrozol , Pós-Menopausa , Purinas , Receptor ErbB-2 , Receptores de Estrogênio , Humanos , Aminopiridinas/administração & dosagem , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Purinas/administração & dosagem , Purinas/efeitos adversos , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Receptores de Estrogênio/metabolismo , Letrozol/administração & dosagem , Letrozol/uso terapêutico , Adulto , China , Idoso , Receptores de Progesterona/metabolismo , Pré-Menopausa , Intervalo Livre de Progressão , Gosserrelina/administração & dosagem , Gosserrelina/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/uso terapêutico , População do Leste AsiáticoRESUMO
Several FDA-approved adjuvants signal through the NLRP3 inflammasome and IL-1ß release. Identifying small molecules that induce IL-1ß release could allow targeted delivery and structure-function optimization, thereby improving safety and efficacy of next-generation adjuvants. In this work, we leverage our existing high throughput data set to identify small molecules that induce IL-1ß release. We find that ribociclib induces IL-1ß release when coadministered with a TLR4 agonist in an NLRP3- and caspase-dependent fashion. Ribociclib was formulated with a TLR4 agonist into liposomes, which were used as an adjuvant in an ovalbumin prophylactic vaccine model. The liposomes induced antigen-specific immunity in an IL-1 receptor-dependent fashion. Furthermore, the liposomes were coadministered with a tumor antigen and used in a therapeutic cancer vaccine, where they facilitated rejection of E.G7-OVA tumors. While further chemical optimization of the ribociclib scaffold is needed, this study provides proof-of-concept for its use as an IL-1 producing adjuvant in various immunotherapeutic contexts.
Assuntos
Quinase 4 Dependente de Ciclina , Inflamassomos , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLR , Purinas , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-1beta/metabolismo , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Animais , Humanos , Camundongos , Purinas/farmacologia , Purinas/química , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T/imunologia , Camundongos Endogâmicos C57BL , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Lipossomos/química , Vacinas Anticâncer/farmacologia , Vacinas Anticâncer/imunologia , Feminino , AminopiridinasRESUMO
Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.
Assuntos
Aminopiridinas , Antineoplásicos , Inibidores de Histona Desacetilases , Pirimidinas , Humanos , Animais , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Aminopiridinas/farmacologia , Aminopiridinas/síntese química , Aminopiridinas/química , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Relação Estrutura-Atividade , Camundongos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Descoberta de Drogas , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Camundongos Endogâmicos BALB C , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos NusRESUMO
Palbociclib and ribociclib an orally bioavailable, potent cyclin-dependent kinase 4/6 inhibitors, with low oral bioavailability due to substrate specificity towards CYP3A and P-glycoprotein. Thus, current research aims to examine the effect of a bioenhancer (naringin), on oral pharmacokinetics of palbociclib and ribociclib. Naringin's affinity for CYP3A4 and P-glycoprotein was studied using molecular docking; its impact on palbociclib/ribociclib CYP3A metabolism and P-glycoprotein-mediated efflux was examined using in vitro preclinical models; and its oral pharmacokinetics in rats were assessed following oral administration of palbociclib/ribociclib in presence of naringin (50 and 100 mg/kg). Naringin binds optimally to both proteins with the highest net binding energy of - 1477.23 and - 1607.47 kcal/mol, respectively. The microsomal intrinsic clearance of palbociclib and ribociclib was noticeably reduced by naringin (5-100 µM), by 3.0 and 2.46-folds, respectively. Similarly, naringin had considerable impact on the intestinal transport and efflux of both drugs. The pre-treatment with 100 mg/kg naringin increased significantly (p < 0.05) the oral exposure of palbociclib (2.0-fold) and ribociclib (1.95-fold). Naringin's concurrent administration of palbociclib and ribociclib increased their oral bioavailability due to its dual inhibitory effect on CYP3A4 and P-glycoprotein; thus, concurrent naringin administration may represent an innovative strategy for enhancing bioavailability of cyclin-dependent kinase inhibitors.
Assuntos
Disponibilidade Biológica , Quinase 6 Dependente de Ciclina , Flavanonas , Inibidores de Proteínas Quinases , Animais , Humanos , Ratos , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Aminopiridinas/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Biomelhoradores/farmacologia , Células CACO-2 , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Citocromo P-450 CYP3A/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Flavanonas/administração & dosagem , Flavanonas/farmacologia , Simulação de Acoplamento Molecular , Permeabilidade , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Purinas/farmacocinética , Purinas/administração & dosagem , Purinas/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Piridinas/administração & dosagem , Ratos Sprague-DawleyRESUMO
BACKGROUND: Abemaciclib was newly approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) high-risk early breast cancer (EBC). Clinical guidelines recommended abemaciclib as the first-line treatment for HR+/ HER2- EBC (early use) or HR+/ HER2- metastatic breast cancer (MBC) (delayed use). OBJECTIVE: To compare the cost-effectiveness of early vs delayed use of abemaciclib for treatment of HR+/HER2- high-risk EBC. Early use was defined as combined abemaciclib and endocrine therapy as first-line therapy for EBC, followed by treatment with fulvestrant for MBC. Delayed use was defined as endocrine therapy for EBC, followed by combined abemaciclib and fulvestrant therapy for MBC. METHODS: A 5-state model was developed to estimate lifetime costs, life-years (LYs), and quality-adjusted life-years (QALYs) of hypothetical patients with HR+/ HER2- EBC from a third-party US payer's perspective. Key clinical and safety data were derived from the monarchE and MONARCH 2 clinical trials. Costs, utilities, and disutility values of adverse events were obtained from the literature. We calculated the incremental cost-effectiveness ratio (ICER) of early vs delayed abemaciclib use and compared it with a willingness-to-pay (WTP) threshold of $100,000 per LY or QALY. Deterministic and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the base-case model. RESULTS: Base-case analysis showed early use yielded 21.08 LYs and 17.93 QALYs for $586,213 and delayed use yielded 11.14 LYs and 9.38 QALYs for $157,576. The ICER of early vs delayed use was $43,136/LY and $50,104/QALY, which was cost-effective at the WTP threshold of $100,000. The PSA result indicated that a 94.6% likelihood of early use (vs delayed use) was cost-effective at the WTP threshold of $100,000 per QALY. CONCLUSIONS: This study suggests that giving abemaciclib in the early stage rather than waiting until patients develop metastatic disease (current standard of care in MBC) is a cost-effective strategy.
Assuntos
Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Benzimidazóis , Neoplasias da Mama , Análise Custo-Benefício , Anos de Vida Ajustados por Qualidade de Vida , Receptor ErbB-2 , Humanos , Benzimidazóis/economia , Benzimidazóis/uso terapêutico , Benzimidazóis/administração & dosagem , Aminopiridinas/economia , Aminopiridinas/uso terapêutico , Aminopiridinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismoRESUMO
BACKGROUND: In luminal breast cancer, adjuvant CDK4/6 inhibitors (eg, abemaciclib) improve invasive disease-free survival. In patients with T1-2, grade 1-2 tumours, and one or two sentinel lymph node metastases, completion axillary lymph node dissection (cALND) is the only prognostic tool available that can reveal four or more nodal metastases (pN2-3), which is the only indication for adjuvant abemaciclib in this setting. However, this technique can lead to substantial arm morbidity in patients. We aimed to pragmatically describe the potential benefit and harm of this strategy on the individual patient level in patients from the ongoing SENOMAC trial. METHODS: In the randomised, phase 3, SENOMAC trial, patients aged 18 years or older, of any performance status, with clinically node-negative T1-T3 breast cancer and one or two sentinel node macrometastases from 67 sites in five European countries (Denmark, Germany, Greece, Italy, and Sweden) were randomly assigned (1:1), via permutated block randomisation (random block size of 2 and 4) stratified by country, to either cALND or its omission (ie, they had a sentinel lymph node biopsy only). The primary outcome is overall survival, which is yet to be reported. In this post-hoc analysis, patients from the SENOMAC per-protocol population, with luminal oestrogen-receptor positive, HER2-negative, T1-2, histological grade 1-2 breast cancer, with tumour size of 5 cm or smaller were selected to match the characteristics of cohort 1 of the monarchE trial who would only have an indication for adjuvant abemaciclib if found to have 4 or more nodal metastases. The primary study objective was to determine the number of patients who developed patient-reported severe or very severe impairment of physical arm function after cALND (as measured by the Lymphedema Functioning, Disability, and Health [Lymph-ICF] Questionnaire) 1 year after surgery to avoid one invasive disease-free survival event at 5 years with 2 years of adjuvant abemaciclib, using invasive disease-free survival event data from cohort 1 of the monarchE trial. The SENOMAC trial is registered with ClincialTrials.gov, NCT02240472, and is closed to accrual and ongoing. FINDINGS: Between Jan 31, 2015, and Dec 31, 2021, 2766 patients were enrolled in SENOMAC and randomly assigned to cALND (n=1384) or sentinel node biopsy only (n=1382), of whom 2540 were included in the per-protocol population. 1705 (67%) of 2540 patients met this post-hoc study's eligibility criteria, of whom 802 (47%) had a cALND and 903 (53%) had a sentinel lymph node biopsy only. Median age at randomisation was 62 years (IQR 52-71), 1699 (>99%) of 1705 patients were female, and six (<1%) were male. Among 1342 patients who responded to questionnaires, after a median follow-up of 45·2 months (IQR 25·6-59·8; data cutoff Nov 17, 2023), patient-reported severe or very severe impairment of physical arm function was reported in 84 (13%) of 634 patients who had cALND versus 30 (4%) of 708 who had sentinel lymph node biopsy only (χ2 test p<0·0001). To avoid one invasive disease-free survival event at 5 years with adjuvant abemaciclib, cALND would need to be performed in 104 patients, and would result in nine patients having severe or very severe impairment of physical arm function 1 year after surgery. INTERPRETATION: As a method to potentially identify an indication for abemaciclib, and subsequently avoid invasive disease-free survival events at 5 years with 2 years of adjuvant abemaciclib, cALND carries a substantial risk of severe or very severe arm morbidity and so cALND should be discouraged for this purpose. FUNDING: Swedish Research Council, the Swedish Cancer Society, the Nordic Cancer Union, and the Swedish Breast Cancer Association.