RESUMEN
Since the US FDA approval of everolimus/exemestane in July 2012, and of the first CDK 4/6 inhibitor, palbociclib, combined with endocrine treatment in February 2015, a third class of therapeutic compounds, the PI3K inhibitors, has been introduced to the arsenal of targeted therapies overcoming endocrine resistance in hormone receptor-positive metastatic breast cancer. Alpelisib (PIQRAY®) is the first of these novel agents yielding promising clinical results, giving an impetus to further development of tailored endocrine anticancer treatments. Herein, we review its pharmacodynamic and pharmacokinetic properties, safety and efficacy data, as well as Phase III SOLAR-1 trial, prompting FDA approval of alpelisib in hormone receptor-positive metastatic breast cancer harboring PIK3CA mutations. Furthermore, implications for clinical use and current research will also be discussed.
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Neoplasias de la Mama/terapia , Fosfatidilinositol 3-Quinasa Clase I/genética , Terapia Neoadyuvante/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Tiazoles/uso terapéutico , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/métodos , Ensayos Clínicos como Asunto , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Mutación , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tiazoles/farmacologíaRESUMEN
Since the US FDA-approval of the first immune checkpoint inhibitor, anticytotoxic T-lymphocyte antigen-4 monoclonal antibody ipilimumab, for metastatic melanoma on 28 March 2011, another six agents have been granted use among a multitude of tumors, including renal cell cancer, Hodgkin lymphoma, urothelial carcinoma and non-small-cell lung cancer. The first anti-programmed cell death ligand-1 monoclonal antibody to receive the FDA approval, atezolizumab (Tecentriq®), has yielded promising results among international Phase III trials in triple-negative breast cancer and small-cell lung cancer, expanding the field of cancer immunotherapies. Herein, we review the pharmacodynamic and pharmacokinetic properties of atezolizumab, its safety and efficacy data from early clinical trials and summarize data from Phase III IMpassion130 trial, prompting FDA and EMA approval of atezolizumab in metastatic triple-negative breast cancer. Finally, implications for clinical use and ongoing research will be briefly discussed.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Albúminas/administración & dosificación , Albúminas/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Dosis Máxima Tolerada , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Supervivencia sin Progresión , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/mortalidad , Neoplasias de la Mama Triple Negativas/patología , Escape del Tumor/efectos de los fármacosRESUMEN
AIM: Cancer remains a disease with a significant impact on morbidity and mortality but also on quality of life. This prospective randomized pilot study investigated the effects of a sound intervention on physical and emotional well-being in outpatients with cancer. METHODS: Two self-applied sound interventions were used for this purpose, either active "music playing" with a body monochord or passive sound intervention with headphones to listen to a given music compilation. Interventions were carried out over a period of 4 weeks for at least 15 min in the evening before bedtime. The following self-assessment questionnaires were completed both at baseline and after 4 weeks to evaluate the response: the Pittsburgh Sleep Quality Index (PSQI), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), Visual Analogue Scale (VAS) for pain and fatigue, and the Fear of Progression (FoP) questionnaire. Primary endpoint of this exploratory trial was to describe the rate of patients with improvement in at least one dimension without worsening of any other. RESULTS: 73 patients (29 male, 44 female) were included in the study and randomized to either active (n = 34, 47%) or passive sound intervention (n = 39, 53%). Median age was 52.0 years (range 21-79). Fourteen patients (19%) stated that they were musically active. The sound intervention was carried out on a median of 26 days (range 5-28). A higher percentage of patients in the passive group reached the primary endpoint: n = 15 (39%) versus n = 9 (27%). Response differences in favour of the passive group were seen with the VAS fatigue and with QLQ-30 questionnaires. Overall, an improvement in QLQ-30 questionnaire was seen in 12 patients (31%) in the passive group versus 3 patients (9%). Moreover, sound intervention significantly improved social functioning and shortness of breath in the passive group according to QLQ-C30. Significant improvements were also noticed in the passive group in terms of affective reactions as a domain of the FoP questionnaire. No effects on pain or sleep quality could be observed. CONCLUSION: A 4-week self-administered sound intervention was feasible in outpatients suffering from cancer. Using a panel of 5 questionnaires, passive sound interventions appeared to be more likely to positively influence patient-reported outcomes. In particular, a positive impact was documented in social functioning and fatigue.
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Neoplasias , Calidad de Vida , Humanos , Masculino , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Proyectos Piloto , Neoplasias/terapia , Neoplasias/psicología , Dolor , Encuestas y Cuestionarios , Fatiga/terapiaRESUMEN
AIM: The present exploratory study investigated the diagnostic value of inflammatory markers in patients with breast cancer to predict anti-tumour treatment-related cardiac events. METHODS: Twenty-one patients with breast cancer were enrolled in this prospective observational study and followed over 6 months. Transthoracic echocardiography and measurement of cardiac (N-terminal prohormone of brain natriuretic peptide (NT-proBNP), troponin I (TnI)) and inflammatory biomarkers (vascular adhesion molecule 1 (VCAM-1), soluble suppression of tumorigenesis-2 (sST2), adiponectin) was performed at 3-month intervals (baseline, follow-up, final visit). Cardiac events were defined as decrease in left ventricular ejection fraction (LVEF, decrease by 10% or <50%) or increase in global longitudinal strain (GLS, increase by 15% or > -16%), as a more sensitive marker of LV function. RESULTS: Cardiac deterioration was observed in 9 out of 21 patients (event group). While LVEF did not differ significantly between the two groups (event vs. no event) at any visit, GLS was significantly higher during follow-up (follow-up: event -16 ± 3.3% vs. no event -18 ± 1.6%, p = 0.04; final visit: event -16 ± 2.1% vs. no event -19 ± 1.9%, p = 0.003). NT-proBNP was numerically higher in patients with a cardiac event during all visits, with NT-proBNP negatively correlated with LVEF and MAPSE (both r = -0.33, p = 0.02), whereas GLS (r = 0.40, p = 0.006), TnI (r = 0.44, p = 0.001), and VCAM-1 (r = 0.48, p = 0.003) showed a positive association with NT-proBNP. In comparison, higher VCAM-1 and sST2 concentrations were detected in the event group at both baseline and the final visit, with a significant difference for baseline (VCAM-1: p = 0.02; sST2: p = 0.03). Adiponectin was also lower in patients with a treatment-related event. Thresholds for VCAM-1 >762 ng/mL and sST2 >18.7 ng/mL, as detected by ROC analysis, correlated best with the primary endpoint. CONCLUSION: Cardiac events during anti-tumour treatment in patients with breast cancer are relatively common. Inflammatory markers such as VCAM-1 or sST2 were associated with an increased likelihood for occurrence of a treatment-related event, which may therefore hold the promise to better identify patients at high risk.
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Neoplasias de la Mama , Péptido Natriurético Encefálico , Adiponectina , Biomarcadores , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Proteína 1 Similar al Receptor de Interleucina-1 , Fragmentos de Péptidos , Proyectos Piloto , Pronóstico , Volumen Sistólico , Troponina I , Molécula 1 de Adhesión Celular Vascular , Función Ventricular IzquierdaRESUMEN
BACKGROUND/AIM: Cardiotoxicity due to antitumor therapy is a dreaded complication and could thus impact the prognosis of patients with breast cancer. This study sought to analyze the occurrence of adverse cardiovascular events and to identify potential risk factors. PATIENTS AND METHODS: A total of 136 patients with breast cancer were divided into two groups based on the occurrence of treatment-related cardiovascular toxicity [event 47 (35%) vs. no event 89 (65%)]. Patients were followed over a median of 45 months (range=37-83 months). RESULTS: Most common events were thromboembolic complications (26%), followed by heart failure (15%) and acute toxic cardiomyopathy (5%), with a reduced left ventricular ejection fraction [LVEF (%), no event 59±5.0 vs. event 55±11, p=0.01 ]. Patients with leftsided breast cancer and an advanced stage disease had a higher risk of developing adverse cardiovascular events. The highest risk was found for patients with a high number of cardiovascular risk factors. In addition to LVEF, mitral annular plane systolic excursion was also significantly reduced in the event group, while there was a trend for higher global longitudinal strain. During follow-up, 26 patients (19.1%) deceased, whereof 12 had a treatment-related cardiovascular event, but without statistical difference. CONCLUSION: Treatment-related cardiovascular events are relatively common in about one third of patients with breast cancer. Women with a cardiovascular risk profile or an advanced stage disease had a higher risk for adverse events. Despite the treatment-related cardiac deterioration, no difference in mortality was observed during follow up.
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Neoplasias de la Mama , Insuficiencia Cardíaca , Neoplasias de la Mama/tratamiento farmacológico , Estudios Transversales , Femenino , Humanos , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
BACKGROUND: CDK4/6 inhibitors have become the standard for first-line treatment of metastatic luminal breast cancer based on consistent data from several phase 3 trials demonstrating clinically meaningful improvement of progression-free as well as overall survival. In addition, they are about to become a part of adjuvant treatment for patients with high-risk luminal disease based on positive results from the first randomized phase 3 trial on abemaciclib. Nevertheless, the majority of patients with advanced or metastatic luminal breast cancer and prospectively a relevant proportion of patients treated in the adjuvant setting will eventually develop resistance to this endocrine based combination within 12-36 months, depending on the line of treatment. CONCLUSION: Potential subsequent therapies include PI3K inhibitors, mTOR inhibitors, endocrine monotherapy, PARP inhibitors, and chemotherapy. However, these therapies have mainly been developed in the pre-CDK4/6 inhibitor era and little is known about potential cross-resistance. The concept of continuing CDK4/6 inhibition beyond progression is supported by some preclinical data, but to date there is very limited clinical evidence to support this strategy. Therefore, treatment of metastatic luminal breast cancer after progression on CDK4/6 inhibitors remains a challenge. KEY MESSAGES: Here we review current evidence from pro- and retrospective studies and give an outlook on future developments with respect to novel therapeutic agents, including oral SERD and AKT inhibitors, which have the potential to change the therapeutic landscape in the future. Furthermore, clinical treatment algorithms and current research will also be discussed.
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BACKGROUND: Music therapy or sound interventions were shown to confer beneficial effects in patients with cancer for instance in terms of pain or fear relief and improvement of other patient reported outcomes. Cardiovascular parameters, especially heart rate variability (HRV) were found to have prognostic implications in cancer patients. In this trial we aimed to investigate the effects of a sound intervention on cardiovascular parameters compared to rest in patients with cancer. METHODS AND RESULTS: Using a randomized cross-over design, 52 patients (male 13, female 39) with cancer were recruited to receive both a 15-minute sound intervention and a 15-minute rest intervention within 4 weeks with at least a one-week blanking period. Cardiovascular parameters (among others HRV, aortic pulse wave velocity [PWV], augmentation index [Aix], aortic blood pressure [BP], heart rate [HR]) were assessed immediately before (pre) and after (post) the intervention had taken place. HRV (Root mean square of successive RR interval differences [RMSSD, ms]) significantly increased, during sound intervention (median RMSSD pre 24 [range 5-112] vs post 22 [range 9-141], P = .03). Likewise, median PWV, as a direct marker of arterial stiffness, was significantly reduced by sound intervention ([m/s] pre 8.5 [range 5.6-19.6] vs post 8.3 [range 5.6-15.6], P = .04). For both parameters no statistically significant change during rest was observed. HR was lowered by both, rest (P < .0001) and sound intervention (P = .02), with a more pronounced effect by rest. A significant increase in systolic aortic blood pressure was shown by rest ([mmHg] median 101 [range 78-150] vs post median 103 [range 71-152], P = .04) but not during sound intervention (P = .59), while rest intervention led to a decrease in resistance index (pre median 33 [range 13-92] vs post median 32 [11-84], P = .02). CONCLUSION: In comparison with rest, a single sound intervention in patients with cancer improved cardiovascular parameters commonly associated with increased stress levels. Studies with longer follow-up and multiple interventions are warranted. TRIAL REGISTRATION: ISRCTN registry 70947363.
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Neoplasias , Rigidez Vascular , Presión Sanguínea , Estudios Cruzados , Femenino , Humanos , Masculino , Neoplasias/terapia , Análisis de la Onda del PulsoRESUMEN
PURPOSE: To investigate the safety, clinical efficacy, virus pharmacokinetics, shedding, and immune response after administration of an oncolytic parvovirus (H-1PV, ParvOryx) to patients with metastatic pancreatic ductal adenocarcinoma (PDAC) refractory to first-line therapy. PATIENTS AND METHODS: This is a noncontrolled, single-arm, open-label, dose-escalating, single-center clinical trial. Seven patients with PDAC and at least one liver metastasis were included. ParvOryx was administered intravenously on 4 consecutive days and as an intralesional injection, 6 to 13 days thereafter. Altogether, three escalating dose levels were investigated. In addition, gemcitabine treatment was initiated on day 28. RESULTS: ParvOryx showed excellent tolerability with no dose-limiting toxicities. One patient had a confirmed partial response and one patient revealed an unconfirmed partial response according to RECIST criteria. Both patients showed remarkably long surivial of 326 and 555 days, respectively. Investigation of pharmacokinetics and virus shedding revealed dose dependency with no excretion of active virus particles in saliva or urine and very limited excretion in feces. H-1PV nucleic acids were detected in tumor samples of four patients. All patients showed T-cell responses to viral proteins. An interesting immunologic pattern developed in tumor tissues and in blood of both patients with partial response suggesting immune activation after administration of ParvOryx. CONCLUSIONS: The trial met all primary objectives, revealed no environmental risks, and indicated favorable immune modulation after administration of ParvOryx. It can be considered a good basis for further systematic clinical development alone or in combination with immunomodulatory compounds.
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Adenocarcinoma/secundario , Adenocarcinoma/terapia , Carcinoma Ductal Pancreático/secundario , Carcinoma Ductal Pancreático/terapia , Parvovirus H-1 , Sistema Inmunológico/inmunología , Viroterapia Oncolítica , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Anciano , Humanos , Persona de Mediana Edad , Viroterapia Oncolítica/efectos adversosRESUMEN
PURPOSE: CATCH (Comprehensive Assessment of clinical feaTures and biomarkers to identify patients with advanced or metastatic breast Cancer for marker driven trials in Humans) is a prospective precision oncology program that uses genomics and transcriptomics to guide therapeutic decisions in the clinical management of metastatic breast cancer. Herein, we report our single-center experience and results on the basis of the first 200 enrolled patients of an ongoing trial. METHODS: From June 2017 to March 2019, 200 patients who had either primary metastatic or progressive disease, with any number of previous treatment lines and at least one metastatic site accessible to biopsy, were enrolled. DNA and RNA from tumor tissue and corresponding blood-derived nontumor DNA were profiled using whole-genome and transcriptome sequencing. Identified actionable alterations were brought into clinical context in a multidisciplinary molecular tumor board (MTB) with the aim of prioritizing personalized treatment recommendations. RESULTS: Among the first 200 enrolled patients, 128 (64%) were discussed in the MTB, of which 64 (50%) were subsequently treated according to MTB recommendation. Of 53 evaluable patients, 21 (40%) achieved either stable disease (n = 13, 25%) or partial response (n = 8, 15%). Furthermore, 16 (30%) of those patients showed improvement in progression-free survival of at least 30% while on MTB-recommended treatment compared with the progression-free survival of the previous treatment line. CONCLUSION: The initial phase of this study demonstrates that precision oncology on the basis of whole-genome and RNA sequencing is feasible when applied in the clinical management of patients with metastatic breast cancer and provides clinical benefit to a substantial proportion of patients.
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Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Medicina de Precisión , Adulto , Anciano , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Femenino , Genoma , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Prospectivos , TranscriptomaRESUMEN
Triple-negative breast cancer constitutes ~ 15% of all breast cancer subtypes. Because of the negative hormone receptor and human epidermal growth factor receptor 2 status, therapy is mainly based on chemotherapy with a poor median overall survival in the metastatic setting of ~ 18 months. Compared to other breast cancer subtypes, triple-negative breast cancer is characterized by a higher mutational load, which renders the tumor immunogenic and amenable to immunotherapeutic intervention. Based on the promising results of immunotherapy in other cancer entities, including melanoma or non-small cell lung cancer, a vast number of studies are currently assessing immunotherapeutic approaches in patients with triple-negative breast cancer. While monotherapies with antibodies against programmed death-1 and programmed death ligand-1 have shown little efficacy in patients with heavily pretreated metastatic triple-negative breast cancer, treatment efficacy likely depends on the therapeutic setting, the treatment line, and the combination of immunotherapies with other anticancer drugs. Several studies are currently evaluating the safety and efficacy of immune checkpoint inhibition in combination with chemotherapy, angiogenesis inhibitors, poly(ADP-ribose) polymerase inhibitors, as well as radiotherapy in the metastatic and (neo-)adjuvant settings. The US Food and Drug Administration approval of nab-paclitaxel in combination with atezolizumab in 2019 presented a landmark therapeutic development for patients with triple-negative breast cancer, given the limited treatment options available for this highly aggressive disease. In this review, we provide an overview on important ongoing and completed immunotherapeutic studies in triple-negative breast cancer and their possible implications for clinical practice.
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Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacologíaRESUMEN
BACKGROUND: Mobile phone video call applications generally did not undergo testing in randomised controlled clinical trials prior to their implementation in patient care regarding the rate of successful patient visits and impact on the physician-patient relationship. METHODS: The National Center for Tumour Diseases (NCT) MOBILE trial was a monocentric open-label randomised controlled clinical trial of patients with solid tumours undergoing systemic cancer therapy with need of a follow-up visit with their consulting physician at outpatient clinics. 66 patients were 1:1 randomised to receive either a standard in-person follow-up visit at outpatient clinics or a video call via a mobile phone application. The primary outcome was feasibility defined as the proportion of patients successfully completing the first follow-up visit. Secondary outcomes included success rate of further video calls, time spent by patient and physician, patient satisfaction and quality of physician-patient relationship. FINDINGS: Success rate of the first follow-up visit in the intention-to-treat cohort was 87.9% (29 of 33) for in-person visits and 78.8% (26 of 33) for video calls (relative risk: RR 0.90, 95% CI 0.70 to 1.13, p=0.51). The most common reasons for failure were software incompatibility in the video call and no-show in the in-person visit arm. The success rate for further video visits was 91.7% (11 of 12). Standardised patient questionnaires showed significantly decreased total time spent and less direct costs for patients (Δmean -170.8 min, 95% CI -246 min to -95.5 min), p<0.0001; Δmean -14.37, 95% CI -23.9 to -4.8, p<0.005) and comparable time spent for physicians in the video call arm (Δmean 0.5 min, 95% CI -5.4 min to 6.4 min, p=0.86). Physician-patient relationship quality mean scores assessed by a validated standardised questionnaire were higher in the video call arm (1.13-fold, p=0.02). INTERPRETATION: Follow-up visits with the tested mobile phone video call application were feasible but software compatibility should be critically evaluated. TRIAL REGISTRATION NUMBER: DRKS00015788.
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Médicos , Telemedicina , Humanos , Oncología Médica , Satisfacción del Paciente , Derivación y ConsultaRESUMEN
ImmunoRNases represent a highly attractive alternative to conventional immunotoxins for cancer therapy. Quantitative production of immunoRNases in appropriate expression systems, however, remains a major challenge for further clinical development of these novel compounds. Here we describe a method for high-level production and purification of a fully functional immunoRNase fusion protein from supernatants of stably transfected mammalian cells.
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Biología Molecular/métodos , Mieloma Múltiple/patología , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/inmunología , Ribonucleasa Pancreática/biosíntesis , Ribonucleasa Pancreática/inmunología , Transfección , Animales , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Células Clonales , Ensayos de Selección de Medicamentos Antitumorales , Citometría de Flujo , Vectores Genéticos/genética , Humanos , Región Variable de Inmunoglobulina/inmunología , Ratones , Proteínas Recombinantes de Fusión/farmacología , Ribonucleasa Pancreática/farmacología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunologíaRESUMEN
Antibody-drug conjugates (ADCs) have evolved as a new class of potent cancer therapeutics. We here report on the development of ADCs with specificity for the B-cell lineage specific (surface) antigen CD22 being expressed in the majority of hematological malignancies. As targeting moiety a previously generated humanized anti-CD22 single-chain variable fragment (scFv) derivative from the monoclonal antibody RFB4 was reengineered into a humanized IgG1 antibody format (huRFB4). Onconase (ranpirnase), a clinically active pancreatic-type ribonuclease, was employed as cytotoxic payload moiety. Chemical conjugation via thiol-cleavable disulfide linkage retained full enzymatic activity and full binding affinity of the ADC. Development of sophisticated purification procedures using size exclusion and ion exchange chromatography allowed the separation of immunoconjugate species with stoichiometrically defined number of Onconase cargos. A minimum of two Onconase molecules per IgG was required for achieving significant in vitro cytotoxicity towards lymphoma and leukemia cell lines. Antibody-drug conjugates with an Onconase to antibody ratio of 3 : 1 exhibited an IC50 of 0.08 nM, corresponding to more than 18,400-fold increased cytotoxicity of the ADC when compared with unconjugated Onconase. These results justify further development of this ADC as a promising first-in-class compound for the treatment of CD22-positive malignancies.