RESUMEN
BACKGROUND: Precision oncology, defined as treatment of patients with targeted therapies matched to specific molecular alterations, has entered routine clinical practice. Particularly in patients with advanced cancer or hematologic malignancies, for whom no further standard therapies are available, this approach is increasingly applied as last resort option outside of the approved indication. However, data on patient outcomes are not systematically collected, analyzed, reported, and shared. We have initiated the INFINITY registry to provide evidence from routine clinical practice to fill this knowledge gap. METHODS: INFINITY is a retrospective, non-interventional cohort study conducted at approximately 100 sites in Germany (office-based oncologists/hematologists and hospitals). We aim to include 500 patients with advanced solid tumors or hematologic malignancies who received a non-standard targeted therapy based on potentially actionable molecular alterations or biomarkers. INFINITY aims to provide insights into the use of precision oncology in routine clinical practice within Germany. We systematically collect details on patient and disease characteristics, molecular testing, clinical decision-making, treatment, and outcome. DISCUSSION: INFINITY will provide evidence on the current biomarker landscape driving treatment decisions in routine clinical care. It will also provide insights on effectiveness of precision oncology approaches in general, and of specific drug class/alteration matches used outside their approved indications. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov, NCT04389541.
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Neoplasias Hematológicas , Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Estudios Retrospectivos , Estudios de Cohortes , Medicina de Precisión , Biomarcadores , Toma de DecisionesRESUMEN
BACKGROUND: Prognosis of patients with multiple myeloma (MM) who have relapsed on or become refractory to immunomodulators and bortezomib is poor, and treatment options are limited. While pomalidomide plus low-dose dexamethasone (POM/DEX) has demonstrated efficacy in clinical trials, real-world evidence is scarce. PATIENTS AND METHODS: POSEIDON was a prospective non-interventional study designed to evaluate effectiveness, safety and quality of life (QoL) of POM/DEX in patients with relapsed or refractory MM (R/RMM) pretreated with at least two prior therapy lines including both lenalidomide and bortezomib in real world in Germany. Patients received POM/DEX according to physicians' choice. Data were analyzed descriptively. RESULTS: Between 2014 and 2017, 151 patients were enrolled, 144 patients with a median of three prior therapy lines qualified for effectiveness analysis. Median age was 73.2 years. Median progression-free and overall survival were 6.3 months [95% confidence interval (CI) 5.2, 8.6] and 12.9 months [95% CI 10.6, 15.1]. Most frequent grade 3/4 adverse events were leukopenia (8.2%), pneumonia (7.5%) and anemia (5.5%). QoL was maintained after start of POM/DEX. CONCLUSION: The results of POSEIDON support the effectiveness and safety of POM/DEX in R/RMM patients pretreated with lenalidomide and bortezomib and highlight the clinical value of the POM/DEX regimen in the real-world setting. Registered at clinicaltrials.gov (NCT02075996).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona , Manejo de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/mortalidad , Calidad de Vida , Recurrencia , Retratamiento , Resultado del TratamientoRESUMEN
The prospective, non-interventional PERFORM study describes and analyzes the effectiveness of palbociclib in combination with endocrine therapy (aromatase inhibitor or fulvestrant) as first-line treatment for patients with locally advanced or metastatic HR+/HER2- breast cancer in the real-world setting in Germany and Austria. PERFORM will reflect current patient characteristics and routine treatment patterns including treatment sequences and time to subsequent (chemo)therapy. Besides, second-line treatment effectiveness and patient-relevant end points such as longitudinal patient-reported outcome measurements beyond disease progression will be analyzed. Accounting for the heterogenous real-world patient population, data on clinicopathologic subgroups underrepresented in clinical trials such as elderly or male will be analyzed. Taken together, PERFORM will close knowledge gaps from clinical trials in real world.
Palbociclib in combination with endocrine therapy is the standard first-line treatment for patients with advanced HR+/HER2- breast cancer. Data from clinical trials have shown high response rates and good tolerability. To support these data and close potential knowledge gaps, we conduct the multicenter, observational PERFORM study to evaluate the effectiveness and patient-reported outcomes in patients with advanced HR+/HER2- breast cancer treated with endocrine-based palbociclib therapy in routine clinical practice in Germany. Clinical Trial Registration: NCT04767594 (ClinicalTrials.gov) Sponsor: Pfizer Pharma GmbH, Linkstraße 10, D-10785 Berlin, Germany.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Humanos , Masculino , Anciano , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptor ErbB-2 , Neoplasias de la Mama/patologíaRESUMEN
Temsirolimus has long been the only approved first-line standard of care (SOC) with overall survival (OS) benefit in poor-risk patients with advanced or metastatic renal cell cancer (mRCC). However, tyrosine kinase inhibitors are also commonly used in clinical practice. Pazopanib is an SOC for first-line mRCC treatment, but for poor-risk patients data are scarce. The FLIPPER (First-Line Pazopanib in Poor-Risk Patients with Metastatic Renal Cell Carcinoma) study aimed to assess efficacy and safety of first-line pazopanib in poor-risk mRCC patients. FLIPPER was a single-arm, multicenter, Phase IV trial. Key inclusion criteria were treatment-naive clear cell, inoperable advanced or mRCC, poor-risk according to MSKCC with slight modification, Karnofsky performance status (KPS) ≥60% and adequate organ function. Oral pazopanib 800 mg was given daily. Primary endpoint was the 6-month progression-free survival rate (PFS6). Secondary endpoints included PFS, OS, overall response rate (ORR), duration of response (DOR) and safety. For analysis, descriptive statistics were used. Between 2012 and 2016, 60 patients had been included. Forty-three patients qualified for safety analyses, 34 for efficacy. Median age was 66 years, 64.7% of patients were poor-risk, 82.4% had a KPS ≤70%. PFS6 was 35.3% (95% CI, 19.7-53.5). Median PFS and OS were 4.5 months (95% CI, 3.6-7.8) and 9.3 months (95% CI, 6.6-22.2), respectively. ORR was 32.4% (95% CI, 17.4-50.5), median DOR 9.7 months (95% CI, 1.8-12.4). The most common treatment-related grade 3/4 adverse event reported in 4.7% of patients was hypertension. No treatment-related death occurred. Since pazopanib is active and well tolerated in poor-risk patients with clear cell mRCC, our results support its use as first-line treatment in this setting.
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Carcinoma de Células Renales/tratamiento farmacológico , Indazoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/patología , Diarrea/inducido químicamente , Fatiga/inducido químicamente , Femenino , Humanos , Hipotiroidismo/inducido químicamente , Indazoles/administración & dosificación , Indazoles/efectos adversos , Estimación de Kaplan-Meier , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Metástasis de la Neoplasia , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Resultado del TratamientoRESUMEN
The ZEB1 transcription factor is best known as an inducer of epithelial-mesenchymal transitions (EMT) in cancer metastasis, acting through transcriptional repression of CDH1 (encoding E-cadherin) and the EMT-suppressing microRNA-200s (miR-200s). Here we analyze roles of the ZEB1 zebrafish orthologs, Zeb1a and Zeb1b, and of miR-200s in control of cell adhesion and morphogenesis during gastrulation and segmentation stages. Loss and gain of function analyses revealed that Zeb1 represses cdh1 expression to fine-tune adhesiveness of migrating deep blastodermal cells. Furthermore, Zeb1 acts as a repressor of epcam in the deep cells of the blastoderm and may contribute to control of epithelial integrity of enveloping layer cells, the outermost cells of the blastoderm. We found a similar ZEB1-dependent repression of EPCAM expression in human pancreatic and breast cancer cell lines, mediated through direct binding of ZEB1 to the EPCAM promoter. Thus, Zeb1 proteins employ several evolutionary conserved mechanisms to regulate cell-cell adhesion during development and cancer.
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Cadherinas/metabolismo , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/fisiología , Glicoproteínas de Membrana/metabolismo , Factores de Transcripción/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/fisiología , Animales , Adhesión Celular , Línea Celular Tumoral , Núcleo Celular/metabolismo , Transición Epitelial-Mesenquimal , Gastrulación , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Hibridación in Situ , MicroARNs/metabolismo , Microscopía Confocal/métodos , Invasividad Neoplásica , Regiones Promotoras Genéticas , Factores de Tiempo , Factores de Transcripción/fisiología , Pez Cebra/embriología , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect persisting after completion of neurotoxic chemotherapies. This observational study was designed to evaluate the effectiveness of the dietary supplement OnLife® (patented mixture of specific fatty acids and palmitoylethanolamide) in improving symptoms of CIPN in breast and colon cancer patients. METHODS: Improvement of CIPN was evaluated in adult patients, previously treated with (neo)adjuvant paclitaxel- (breast cancer) or oxaliplatin-based (colon cancer) therapies, receiving OnLife® for 3 months after completion of chemotherapy. The primary endpoint was to compare the severity of peripheral sensory neuropathy (PSN) and peripheral motor neuropathy (PMN) before and at the end of OnLife® treatment. Secondary endpoints included the assessment of patient-reported quality of life and CIPN symptoms as assessed by questionnaires. RESULTS: 146 patients (n = 75 breast cancer patients and n = 71 colon cancer patients) qualified for analysis; 31.1% and 37.5% of breast cancer patients had an improvement of PSN and PMN, respectively. In colon cancer patients, PSN and PMN improved in 16.9% and 20.0% of patients, respectively. According to patient-reported outcomes, 45.9% and 37.5% of patients with paclitaxel-induced PSN and PMN, and 23.9% and 22.0% of patients with oxaliplatin-induced PSN and PMN experienced a reduction of CIPN symptoms, respectively. CONCLUSION: OnLife® treatment confirmed to be beneficial in reducing CIPN severity and in limiting the progression of neuropathy, more markedly in paclitaxel-treated patients and also in patients with oxaliplatin-induced CIPN.
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Antineoplásicos , Neoplasias del Colon , Enfermedades del Sistema Nervioso Periférico , Adulto , Antineoplásicos/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Humanos , Oxaliplatino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Calidad de VidaRESUMEN
Cancers are heterogeneous by nature. While traditional oncology screens commonly use a single endpoint of cell viability, altering the phenotype of tumor-initiating cells may reveal alternative targets that regulate cellular growth by processes other than apoptosis or cell division. We evaluated the impact of knocking down expression of 420 kinases in bi-lineage triple-negative breast cancer (TNBC) cells that express characteristics of both myoepithelial and luminal cells. Knockdown of ERN1 or ALPK1 induces bi-lineage MDA-MB-468 cells to lose the myoepithelial marker keratin 5 but not the luminal markers keratin 8 and GATA3. In addition, these cells exhibit increased ß-casein production. These changes are associated with decreased proliferation and clonogenicity in spheroid cultures and anchorage-independent growth assays. Confirmation of these assays was completed in vivo, where ERN1- or ALPK1-deficient TNBC cells are less tumorigenic. Finally, treatment with K252a, a kinase inhibitor active on ERN1, similarly impairs anchorage-independent growth of multiple breast cancer cell lines. This study supports the strategy to identify new molecular targets for types of cancer driven by cells that retain some capacity for normal differentiation to a non-tumorigenic phenotype. ERN1 and ALPK1 are potential targets for therapeutic development.
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Diferenciación Celular , Endorribonucleasas/metabolismo , Células Madre Neoplásicas/enzimología , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias de la Mama Triple Negativas/enzimología , Animales , Antineoplásicos/farmacología , Carbazoles/farmacología , Caseínas/genética , Caseínas/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular , Relación Dosis-Respuesta a Droga , Endorribonucleasas/antagonistas & inhibidores , Endorribonucleasas/genética , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Alcaloides Indólicos/farmacología , Queratina-5/genética , Queratina-5/metabolismo , Ratones Endogámicos NOD , Ratones SCID , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Fenotipo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Interferencia de ARN , Transducción de Señal , Factores de Tiempo , Transfección , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Carga TumoralRESUMEN
Invasion and metastasis of carcinomas is promoted by the activation of the embryonic 'epithelial to mesenchymal transition' (EMT) program, which triggers cellular mobility and subsequent dissemination of tumour cells. We recently showed that the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) is a crucial promoter of metastasis and demonstrated that ZEB1 inhibits expression of the microRNA-200 (miR-200) family, whose members are strong inducers of epithelial differentiation. Here, we report that ZEB1 not only promotes tumour cell dissemination, but is also necessary for the tumour-initiating capacity of pancreatic and colorectal cancer cells. We show that ZEB1 represses expression of stemness-inhibiting miR-203 and that candidate targets of miR-200 family members are also stem cell factors, such as Sox2 and Klf4. Moreover, miR-200c, miR-203 and miR-183 cooperate to suppress expression of stem cell factors in cancer cells and mouse embryonic stem (ES) cells, as demonstrated for the polycomb repressor Bmi1. We propose that ZEB1 links EMT-activation and stemness-maintenance by suppressing stemness-inhibiting microRNAs (miRNAs) and thereby is a promoter of mobile, migrating cancer stem cells. Thus, targeting the ZEB1-miR-200 feedback loop might form the basis of a promising treatment for fatal tumours, such as pancreatic cancer.
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Diferenciación Celular , Proteínas de Homeodominio/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , MicroARNs/genética , Neoplasias/metabolismo , Factores de Transcripción/metabolismo , Animales , Secuencia de Bases , Línea Celular Tumoral , Células Epiteliales/citología , Células Epiteliales/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Humanos , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Desnudos , Neoplasias/genética , Neoplasias/patología , Alineación de Secuencia , Ensayos Antitumor por Modelo de Xenoinjerto , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
Recent data suggest proteases of the papain-like cysteine cathepsin family as molecular targets for cancer therapy. Here, we report the treatment of polyoma middle T oncogene-induced breast cancers in mice with the cell-permeable broad-spectrum cysteine cathepsin inhibitor JPM-OEt. Up to 100 mg/kg inhibitor was intraperitoneally injected once per day in two trials on early and advanced cancers. In both trials, transient delays in tumour growth were observed. However, at the endpoint of both experiments no significant differences in tumour weights, histopathology and lung metastasis were found between the inhibitor and the control group. The invasive strand formation of collagen I-embedded tumour cell spheroids generated from primary tumours of inhibitor-treated mice in the early cancer trial could be inhibited in vitro by JPM-OEt; a result arguing against induction of resistance to the inhibitor. Measurement of cysteine cathepsin activities in tissue extracts after intraperitoneal injection of JPM-OEt revealed effective inhibition of cysteine cathepsins in pancreas, kidneys and liver, while activities in mammary cancers and in lungs were not significantly affected. We conclude that the pharmacokinetic properties of JPM-OEt, which result in poor bioavailability, may prohibit its use for stand-alone treatment of solid mammary cancers and their lung metastases.