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PURPOSE: Triple-negative breast cancer (TNBC) is a heterogenous disease that carries the poorest prognosis of all breast cancers. Although novel TNBC therapies in development are frequently targeted towards tumors carrying a specific genomic, transcriptomic, or protein biomarker, how these biomarkers are correlated is poorly understood. EXPERIMENTAL DESIGN: To better understand the molecular features of TNBC and their correlation with one another, we performed multi-modal profiling on a cohort of 95 TNBCs. Our approach involved quantifying tumor-infiltrating lymphocytes through H&E staining, assessing the abundance of retinoblastoma (Rb), androgen receptor (AR), and PD-L1 proteins through immunohistochemistry, and carrying out transcriptomic profiling using the Nanostring BC360 platform, targeted DNA sequencing on a subset of cases, as well as evaluating associations with overall survival. RESULTS: Levels of RB1 mRNA and RB protein are better correlated with markers of Rb functionality than is RB1 mutational status. Luminal AR tumors clustered into two groups with transcriptomes that cluster with either basal or mesenchymal tumors. Tumors classified as PD-L1-positive by presence of immune or tumor cells showed similar biological characteristics. HER2-low TNBC showed no distinct biological phenotype when compared to HER2-zero. The majority of TNBCs classified as basal or HER2-enriched by PAM50, the latter showing significantly improved overall survival. CONCLUSIONS: Our study contributes new insights into biomarker utility for identifying suitable TNBC therapies and the intercorrelations between genomic, transcriptomic, protein, and cellular biomarkers. Additionally, our rich data resource can be used by other researchers to explore the interplay between DNA, RNA, and protein biomarkers in TNBC.
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Chemotherapy is used as neoadjuvant therapy for all subgroups of breast cancer, including ER-positive, and HER2-negative cases. However, studies have suggested that using aromatase inhibitors combined with CDK4/6-inhibitors might be an appropriate alternative in selected patients. Thus, the NEOLETRIB trial evaluates the response of ER-positive, HER2-negative luminal A/B breast cancer to the combination of letrozole and ribociclib in the neoadjuvant setting. Comprehensive molecular biology procedures, including sequential single-cell RNA-sequencing of tumor biopsies, are performed during 6 months of treatment with extensive biobanking of blood samples, tumor biopsies and gut microbiome specimens. Our findings will hopefully contribute to an improved selection of patients who may benefit from this drug combination and give new insights into the intra-tumoral changes during this treatment.Trial registration number: NCT05163106 (ClinicalTrials.gov).
[Box: see text].
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Peripheral CD8+ T cell tolerance is a checkpoint in both autoimmune disease and anti-cancer immunity. Despite its importance, the relationship between tolerance-induced states and other CD8+ T cell differentiation states remains unclear. Using flow cytometric phenotyping, single-cell RNA sequencing (scRNA-seq), and chromatin accessibility profiling, we demonstrated that in vivo peripheral tolerance to a self-antigen triggered a fundamentally distinct differentiation state separate from exhaustion, memory, and functional effector cells but analogous to cells defectively primed against tumors. Tolerant cells diverged early and progressively from effector cells, adopting a transcriptionally and epigenetically distinct state within 60 h of antigen encounter. Breaching tolerance required the synergistic actions of strong T cell receptor (TCR) signaling and inflammation, which cooperatively induced gene modules that enhanced protein translation. Weak TCR signaling during bystander infection failed to breach tolerance due to the uncoupling of effector gene expression from protein translation. Thus, tolerance engages a distinct differentiation trajectory enforced by protein translation defects.
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Linfocitos T CD8-positivos , Diferenciación Celular , Tolerancia Inmunológica , Biosíntesis de Proteínas , Receptores de Antígenos de Linfocitos T , Linfocitos T CD8-positivos/inmunología , Animales , Diferenciación Celular/inmunología , Ratones , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Tolerancia Inmunológica/inmunología , Biosíntesis de Proteínas/inmunología , Transducción de Señal/inmunología , Ratones Endogámicos C57BL , Autoantígenos/inmunologíaRESUMEN
PURPOSE: The monarcHER trial has shown that abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, combined with fulvestrant and trastuzumab, improves progression-free survival (PFS) in hormone receptor-positive (HR+), HER2-positive (HER2+) advanced breast cancer (ABC) compared with standard-of-care (SOC) chemotherapy combined with trastuzumab. We report the final overall survival (OS) analysis, updated safety and efficacy data, and exploratory biomarker results from monarcHER. PATIENTS AND METHODS: monarcHER (NCT02675231), a randomized, multicenter, open-label, phase II trial, enrolled 237 patients across Arm A (abemaciclib, trastuzumab, fulvestrant), Arm B (abemaciclib, trastuzumab), and Arm C (SOC chemotherapy, trastuzumab). Following the statistical plan, OS and PFS were estimated in all arms. RNA sequencing (RNA-seq) was performed on archival tissue. RESULTS: Median OS was 31.1 months in Arm A, 29.2 months in Arm B, and 20.7 months in Arm C [A vs. C: HR, 0.71; 95% confidence interval (CI), 0.48-1.05; nominal two-sided P value 0.086; B vs. C: HR 0.83 (95% CI, 0.57-1.23); nominal two-sided P value 0.365]. Updated PFS and safety findings were consistent with previous results. The most frequently reported treatment-emergent adverse events included diarrhea, fatigue, nausea, neutrophil count decrease, and anemia. In exploratory RNA-seq analyses, Luminal subtypes were associated with longer PFS [8.6 vs. 5.4 months (HR, 0.54; 95% CI, 0.38-0.79)] and OS [31.7 vs. 19.7 months (HR, 0.68; 95% CI, 0.46-1.00)] compared with non-Luminal. CONCLUSIONS: In this phase II trial, abemaciclib + trastuzumab ± fulvestrant numerically improved median OS in women with HR+, HER2+ ABC compared with SOC chemotherapy + trastuzumab.
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Neoplasias de la Mama , Humanos , Femenino , Trastuzumab/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Fulvestrant/uso terapéutico , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance to CDK4/6 inhibitors (CDK4/6i). The precise impact of pharmacologic inhibition of CDK2 is not known due to the lack of selective CDK2 inhibitors. Here we describe INX-315, a novel and potent CDK2 inhibitor with high selectivity over other CDK family members. Using cell-based assays, patient-derived xenografts (PDX), and transgenic mouse models, we show that INX-315 (i) promotes retinoblastoma protein hypophosphorylation and therapy-induced senescence (TIS) in CCNE1-amplified tumors, leading to durable control of tumor growth; (ii) overcomes breast cancer resistance to CDK4/6i, restoring cell cycle control while reinstating the chromatin architecture of CDK4/6i-induced TIS; and (iii) delays the onset of CDK4/6i resistance in breast cancer by driving deeper suppression of E2F targets. Our results support the clinical development of selective CDK2 inhibitors. SIGNIFICANCE: INX-315 is a novel, selective inhibitor of CDK2. Our preclinical studies demonstrate activity for INX-315 in both CCNE1-amplified cancers and CDK4/6i-resistant breast cancer. In each case, CDK2 inhibition induces cell cycle arrest and a phenotype resembling cellular senescence. Our data support the development of selective CDK2 inhibitors in clinical trials. See related commentary by Watts and Spencer, p. 386. This article is featured in Selected Articles from This Issue, p. 384.
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Neoplasias de la Mama , Animales , Ratones , Humanos , Femenino , Quinasa 2 Dependiente de la Ciclina/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Puntos de Control del Ciclo Celular , Senescencia Celular , Cromatina , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina , Ratones TransgénicosRESUMEN
WHAT IS THIS SUMMARY ABOUT?: This article summarizes the results of a study called monarcHER. The study included participants with a certain type of aggressive breast cancer called HR+, HER2+ advanced breast cancer (ABC) that had their disease worsen or return after multiple previous therapies. This summary intends to help you understand the impact of a non-chemotherapy treatment called abemaciclib in people with HR+, HER2+ ABC. When the study was planned, HER2-targeted therapy (ie trastuzumab) was standard treatment and was typically combined with chemotherapy and endocrine therapy (ie fulvestrant). However drug resistance can develop when HER2+ targeted therapy is used for a long time, making it less effective and allowing cancer to grow or spread to other parts of the body. When this happens, few chemotherapy-free options are available. Because of the chemotherapy side effects, this is not desirable. There is an urgent need to develop new, effective, safe, and tolerable treatment options for patients with HR+, HER2+ ABC. The monarcHER study compared the effects of abemaciclib plus trastuzumab with or without fulvestrant compared to the standard of care treatment. WHAT WERE THE RESULTS?: Participants were randomly assigned to 1 of 3 groups: Group A (abemaciclib, trastuzumab and fulvestrant), Group B (abemaciclib and trastuzumab), or Group C (trastuzumab and standard of care chemotherapy). The study compared the length of time patients took study treatments without worsening or dying from their breast cancer. This is called the progression free survival (PFS). Participants in Group A had a longer median PFS than those in groups B and C (8.3 months, 5.7 months and 5.7 months respectively). There was no notable difference in PFS between participants in Groups B and C. Additionally, the study looked at the side effects with each treatment group. The most common side effect which is considered severe or lifethreatening was neutropenia, defined as decreased white blood cell levels. Neutropenia may lead to an increased risk of getting infections. However, the percentage of patients experiencing neutropenia was similar in all groups A, B and C (27%, 22% and 26%, respectively). Patients in groups A (79%) and B (78%) who received abemaciclib experienced similar rates of diarrhea. WHAT DO THE RESULTS MEAN?: The data from the monarcHER study suggest that the combination of abemaciclib, trastuzumab, and fulvestrant may offer a chemotherapy-free option for patients with HR+, HER2+ ABC who have experienced worsening of disease despite multiple prior therapies.
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Neoplasias de la Mama , Neutropenia , Femenino , Humanos , Fulvestrant/uso terapéutico , Trastuzumab/uso terapéutico , Receptor ErbB-2 , Neutropenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The steady, incremental improvements in outcomes for both early-stage and advanced breast cancer patients are, in large part, attributable to the success of novel systemic therapies. In this review, we discuss key conceptual paradigms that have underpinned this success including (1) targeting the driver: the identification and targeting of major oncoproteins in breast cancers; (2) targeting the lineage pathway: inhibition of those pathways that drive normal mammary epithelial cell proliferation that retain importance in cancer; (3) targeting precisely: the application of molecular classifiers to refine therapy selection for specific cancers, and of antibody-drug conjugates to pinpoint tumor and tumor promoting cells for eradication; and (4) exploiting synthetic lethality: leveraging unique vulnerabilities that cancer-specific molecular alterations induce. We describe promising examples of novel therapies that have been discovered within each of these paradigms and suggest how future drug development efforts might benefit from the continued application of these principles.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación CelularRESUMEN
We performed single-cell RNA-sequencing and T cell receptor clonotype tracking of breast and ovarian cancer patients treated with the CDK4/6 inhibitor ribociclib and PD-1 blockade. We highlight evidence of two orthogonal treatment-associated phenomena: expansion of T cell effector populations and promotion of T cell memory formation. Augmentation of the antitumor memory pool by ribociclib boosts the efficacy of subsequent PD-1 blockade in mouse models of melanoma and breast cancer, pointing toward sequential therapy as a potentially safe and synergistic strategy in patients.
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Melanoma , Receptor de Muerte Celular Programada 1 , Animales , Ratones , Aminopiridinas/farmacología , PurinasRESUMEN
Triple-negative breast cancer (TNBC) is an aggressive malignancy for which cytotoxic chemotherapy remains the backbone of treatment. Trilaciclib is an intravenous cyclin-dependent kinase 4/6 inhibitor that induces transient cell cycle arrest of hematopoietic stem and progenitor cells and immune cells during chemotherapy exposure, protecting them from chemotherapy-induced damage and enhancing immune activity. Administration of trilaciclib prior to gemcitabine plus carboplatin (GCb) significantly improved overall survival (OS) compared with GCb alone in an open-label phase II trial in patients with metastatic TNBC, potentially through protection and direct activation of immune function. The randomized, double-blind, placebo-controlled, phase III PRESERVE 2 trial will evaluate the efficacy and safety of trilaciclib administered prior to GCb in patients with locally advanced unresectable or metastatic TNBC. Clinical Trial Registration: NCT04799249 (ClinicalTrials.gov).
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Gemcitabina , Neoplasias de la Mama Triple Negativas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/uso terapéutico , Pirimidinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+) breast cancer (BC). In metastatic disease, strategies involving endocrine therapy combined with CDK4 and 6 inhibitors (CDK4 and 6i) improve clinical outcomes in HR+ BCs. CDK4 and 6i prevent retinoblastoma tumor suppressor protein phosphorylation, thereby blocking the transcription of E2F target genes, which in turn inhibits both mitogen and estrogen-mediated cell proliferation. In this review, we summarize preclinical data pertaining to the use of CDK4 and 6i in BC, with a particular focus on several of the unique chemical, pharmacologic, and mechanistic properties of abemaciclib. As research efforts elucidate the novel mechanisms underlying abemaciclib activity, potential new applications are being identified. For example, preclinical studies have demonstrated abemaciclib can exert antitumor activity against multiple tumor types and can cross the blood-brain barrier. Abemaciclib has also demonstrated distinct activity as a monotherapeutic in the treatment of BC. Accordingly, we also discuss how a greater understanding of mechanisms related to CDK4 and 6 blockade highlight abemaciclib's unique in-class properties, and could pave new avenues for enhancing its therapeutic efficacy.
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Neoplasias de la Mama , Mitógenos , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Bencimidazoles , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Estrógenos , Femenino , Humanos , Mitógenos/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Supresoras de TumorRESUMEN
Background: Inflammatory breast cancer (IBC) is a rare and understudied disease, with 40% of cases presenting with human epidermal growth factor receptor 2 (HER2)-positive subtype. The goals of this study were to (i) assess the pathologic complete response (pCR) rate of short-term neoadjuvant dual-HER2-blockade and paclitaxel, (ii) contrast baseline and on-treatment transcriptional profiles of IBC tumor biopsies associated with pCR, and (iii) identify biological pathways that may explain the effect of neoadjuvant therapy on tumor response. Patients and Methods: A single-arm phase II trial of neoadjuvant trastuzumab (H), pertuzumab (P), and paclitaxel for 16 weeks was completed among patients with newly diagnosed HER2-positive IBC. Fresh-frozen tumor biopsies were obtained pretreatment (D1) and 8 days later (D8), following a single dose of HP, prior to adding paclitaxel. We performed RNA-sequencing on D1 and D8 tumor biopsies, identified genes associated with pCR using differential gene expression analysis, identified pathways associated with pCR using gene set enrichment and gene expression deconvolution methods, and compared the pCR predictive value of principal components derived from gene expression profiles by calculating and area under the curve for D1 and D8 subsets. Results: Twenty-three participants were enrolled, of whom 21 completed surgery following neoadjuvant therapy. Paired longitudinal fresh-frozen tumor samples (D1 and D8) were obtained from all patients. Among the 21 patients who underwent surgery, the pCR and the 4-year disease-free survival were 48% (90% CI 0.29-0.67) and 90% (95% CI 66-97%), respectively. The transcriptional profile of D8 biopsies was found to be more predictive of pCR (AUC = 0.91, 95% CI: 0.7993-1) than the D1 biopsies (AUC = 0.79, 95% CI: 0.5905-0.9822). Conclusions: In patients with HER2-positive IBC treated with neoadjuvant HP and paclitaxel for 16 weeks, gene expression patterns of tumor biopsies measured 1 week after treatment initiation not only offered different biological information but importantly served as a better predictor of pCR than baseline transcriptional analysis. Trial Registration: ClinicalTrials.gov identifier: NCT01796197 (https://clinicaltrials.gov/ct2/show/NCT01796197); registered on February 21, 2013.
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Cyclin-dependent kinase 4 (CDK4) and CDK6 are critical mediators of cellular transition into S phase and are important for the initiation, growth and survival of many cancer types. Pharmacological inhibitors of CDK4/6 have rapidly become a new standard of care for patients with advanced hormone receptor-positive breast cancer. As expected, CDK4/6 inhibitors arrest sensitive tumour cells in the G1 phase of the cell cycle. However, the effects of CDK4/6 inhibition are far more wide-reaching. New insights into their mechanisms of action have triggered identification of new therapeutic opportunities, including the development of novel combination regimens, expanded application to a broader range of cancers and use as supportive care to ameliorate the toxic effects of other therapies. Exploring these new opportunities in the clinic is an urgent priority, which in many cases has not been adequately addressed. Here, we provide a framework for conceptualizing the activity of CDK4/6 inhibitors in cancer and explain how this framework might shape the future clinical development of these agents. We also discuss the biological underpinnings of CDK4/6 inhibitor resistance, an increasingly common challenge in clinical oncology.
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Neoplasias de la Mama , Inhibidores de Proteínas Quinasas , Neoplasias de la Mama/metabolismo , Ciclo Celular , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Femenino , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Pharmacological inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are now an established standard of care for patients with advanced hormone receptor-positive breast cancer. The canonical mechanism underlying CDK4/6 inhibitor activity is the suppression of phosphorylation of the retinoblastoma tumor suppressor protein, which serves to prevent cancer cell proliferation. Recent data suggest that these agents induce other diverse effects within both tumor and stromal compartments, which serve to explain aspects of their clinical activity. Here, we review these phenomena and discuss how they might be leveraged in the development of novel CDK4/6 inhibitor-containing combination treatments. We also briefly review the various known mechanisms of acquired resistance in the clinical setting.
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Neoplasias de la Mama , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Femenino , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Breast cancer is a heterogenous disease with variability in tumor cells and in the surrounding tumor microenvironment (TME). Understanding the molecular diversity in breast cancer is critical for improving prediction of therapeutic response and prognostication. High-plex spatial profiling of tumors enables characterization of heterogeneity in the breast TME, which can holistically illuminate the biology of tumor growth, dissemination and, ultimately, response to therapy. The GeoMx Digital Spatial Profiler (DSP) enables researchers to spatially resolve and quantify proteins and RNA transcripts from tissue sections. The platform is compatible with both formalin-fixed paraffin-embedded and frozen tissues. RNA profiling was developed at the whole transcriptome level for human and mouse samples and protein profiling of 100-plex for human samples. Tissue can be optically segmented for analysis of regions of interest or cell populations to study biology-directed tissue characterization. The GeoMx Breast Cancer Consortium (GBCC) is composed of breast cancer researchers who are developing innovative approaches for spatial profiling to accelerate biomarker discovery. Here, the GBCC presents best practices for GeoMx profiling to promote the collection of high-quality data, optimization of data analysis and integration of datasets to advance collaboration and meta-analyses. Although the capabilities of the platform are presented in the context of breast cancer research, they can be generalized to a variety of other tumor types that are characterized by high heterogeneity.
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Patients with HER2+ metastatic breast cancer are often treated with a multitude of therapies in the metastatic setting, and additional strategies to prolong responses to anti-HER2 therapies are needed. Preclinical evidence suggests synergy between cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors and anti-HER2 therapies. We conducted a phase 1b study of ribociclib and ado-trastuzumab emtansine (T-DM1) in patients with advanced/metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane in any setting, with four or fewer prior lines of therapy in the metastatic setting. A standard 3 + 3 dose-escalation design was used to evaluate various doses of ribociclib in combination with T-DM1, starting at 300 mg. The primary objective was to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D) of ribociclib in combination with T-DM1. A total of 12 patients were enrolled. During dose-escalation, patients received doses of ribociclib of 300 mg (n = 3), 400 mg (n = 3), 500 mg (n = 3), and 600 mg (n = 3). No dose-limiting toxicities were observed. The majority of toxicities were Grade 1 and 2, and the most common Grade 3 toxicities were neutropenia (33%), leukopenia (33%), and anemia (25%). After a median follow-up of 12.4 months, the median PFS was 10.4 months (95% confidence interval, 2.7-19.3). Based on the pharmacokinetic analysis, adverse events, and dose reductions, 400 mg was determined to be the RP2D for ribociclib given on days 8-21 of a 21-day cycle with T-DM1.
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CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8+ T cells during early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition upregulated MXD4, a negative regulator of MYC, in both mouse and human CD8+ T cells. Silencing of Mxd4 or Myc in mouse CD8+ T cells demonstrated the importance of this axis for memory formation. We used single-cell transcriptional profiling and T-cell receptor clonotype tracking to evaluate recently activated human CD8+ T cells in patients with breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8+ memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in patients with cancer may augment long-term protective immunity. SIGNIFICANCE: CDK4/6 inhibition skews newly activated CD8+ T cells toward a memory phenotype in mice and humans with breast cancer. CDK4/6 inhibitors may have broad utility outside breast cancer, particularly in the neoadjuvant setting to augment CD8+ T-cell priming to tumor antigens prior to dosing with checkpoint blockade.This article is highlighted in the In This Issue feature, p. 2355.
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Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Aminopiridinas/uso terapéutico , Animales , Bencimidazoles/uso terapéutico , Neoplasias de la Mama/patología , Neoplasias de la Mama Masculina/tratamiento farmacológico , Neoplasias de la Mama Masculina/patología , Linfocitos T CD8-positivos/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/uso terapéuticoRESUMEN
Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses, and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that is enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several Activator Protein-1 (AP-1) transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors.
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Neoplasias de la Mama , Factor de Transcripción AP-1 , Animales , Neoplasias de la Mama/tratamiento farmacológico , Puntos de Control del Ciclo Celular , Quinasa 4 Dependiente de la Ciclina/genética , Femenino , Genes cdc , Humanos , Ratones , Factor de Transcripción AP-1/genéticaRESUMEN
BACKGROUND: The enhanced knowledge of cancer biology has led to considerable advancement in systemic therapy for advanced breast cancer. Recently, studies showed that cyclin-dependent kinase (CDK) 4/6 inhibitor, when added to endocrine therapy, had improved the outcomes of patients with advanced ER-positive HER2-negative breast cancer. However, the disease often progresses following a period of treatment response. In a subset of patients, disease progression may occur at limited sites, i.e., oligoprogressive disease (OPD). In the past few years, stereotactic radiotherapy (SRT) has emerged as a safe and effective treatment for advanced cancer when delivered to limited metastatic sites. Hence, it is worth investigating the role of SRT in the setting of oligoprogressive breast cancer. METHOD: AVATAR is a multicentre phase II registry trial of SRT with endocrine therapy and CDK 4/6 inhibitor for the management of advanced ER-positive HER2-negative breast cancer. The study aims to enrol 32 patients with OPD limited to 5 lesions. The primary endpoint of the study is time to change systemic therapy measured from the commencement of SRT to change in systemic therapy. Secondary objectives include overall survival, progression free survival and treatment related toxicity. The exploratory objective is to describe the time to change in systemic therapy by the site (bone only vs. non-bone lesions) and number (1 vs. > 1) of OPD. DISCUSSION: This study aims to explore the effect of SRT in maximising the benefit of systemic therapy in patients with oligoprogressive ER-positive HER2-negative breast cancer. This approach might help reduce the burden of disease and improve the life quality in these patients. TRIAL REGISTRATION: ACTRN, ACTRN12620001212943 . Date of registration 16 November 2020- Retrospectively registered.
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Neoplasias de la Mama/radioterapia , Radiocirugia/métodos , Receptores de Estrógenos/análisis , Neoplasias de la Mama/química , Neoplasias de la Mama/mortalidad , Femenino , Humanos , Radiocirugia/efectos adversos , Receptor ErbB-2/análisisRESUMEN
Two recent papers from the laboratory of Professor Ming Li demonstrate that inhibition of transforming growth factor ß specifically in CD4+ T cells can suppress tumor growth through an unanticipated mechanism.