RESUMEN
BACKGROUND: In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study. METHODS: In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1, BRCA2, or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review. RESULTS: Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea. CONCLUSIONS: The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.).
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Antineoplásicos , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Indoles/uso terapéutico , Supervivencia sin Progresión , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/secundario , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos/uso terapéutico , Docetaxel/uso terapéutico , Progresión de la Enfermedad , Genes BRCA1 , Genes BRCA2RESUMEN
BACKGROUND: Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug. METHODS: We report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS: At a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred. CONCLUSIONS: This 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Melanoma , Proteínas Recombinantes de Fusión , Neoplasias de la Úvea , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígenos HLA-A , Melanoma/tratamiento farmacológico , Melanoma/mortalidad , Melanoma/secundario , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/mortalidad , Neoplasias de la Úvea/secundario , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
BACKGROUND: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. METHODS: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. CONCLUSIONS: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
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Antineoplásicos/uso terapéutico , Melanoma/secundario , Proteínas Recombinantes de Fusión/uso terapéutico , Neoplasias de la Úvea/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/efectos adversos , Síndrome de Liberación de Citoquinas/inducido químicamente , Dacarbazina/uso terapéutico , Exantema/inducido químicamente , Femenino , Humanos , Ipilimumab/uso terapéutico , Masculino , Melanoma/tratamiento farmacológico , Melanoma/mortalidad , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/efectos adversos , Análisis de Supervivencia , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/mortalidadRESUMEN
The tumor immune microenvironment is a main contributor to cancer progression and a promising therapeutic target for oncology. However, immune microenvironments vary profoundly between patients, and biomarkers for prognosis and treatment response lack precision. A comprehensive compendium of tumor immune cells is required to pinpoint predictive cellular states and their spatial localization. We generated a single-cell tumor immune atlas, jointly analyzing published data sets of >500,000 cells from 217 patients and 13 cancer types, providing the basis for a patient stratification based on immune cell compositions. Projecting immune cells from external tumors onto the atlas facilitated an automated cell annotation system. To enable in situ mapping of immune populations for digital pathology, we applied SPOTlight, combining single-cell and spatial transcriptomics data and identifying colocalization patterns of immune, stromal, and cancer cells in tumor sections. We expect the tumor immune cell atlas, together with our versatile toolbox for precision oncology, to advance currently applied stratification approaches for prognosis and immunotherapy.
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Neoplasias , Biomarcadores de Tumor/genética , Humanos , Inmunoterapia , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisión , Pronóstico , Microambiente TumoralRESUMEN
Uveal melanoma (UM) is a rare ocular tumor characterized by high metastasis risk and poor prognosis. The in-depth characterization of UM's molecular profile is critical for better disease classification and prognosis. Furthermore, the development of detection tools to monitor UM evolution upon treatment is of great interest for designing optimal therapeutic strategies. However, commonly used techniques, such as ddPCR or NGS, are costly, and they involve sophisticated equipment and complex experimental design. The development of alternative sensing methods that are fast, simple, and inexpensive would be of great benefit to improve UM's diagnosis and management, especially when combined with liquid biopsy. Samples from liquid biopsy can be obtained with minimal invasiveness, and the detection of circulating tumor DNA (ctDNA) in UM patients' plasma has proven useful for the diagnosis of metastasis, prognosis prediction, and disease monitoring. In this context, CRISPR/Cas12a-derived molecular sensors, thanks to their high specificity and sensitivity and their potential for point of care diagnosis, are particularly interesting. Here, we developed a CRISPR/Cas12a-based approach for the specific detection of the UM-related mutation GNAQ Q209P that relies on the design of highly specific crRNAs. Coupled with allele-specific PCR, it constitutes a sensitive platform for liquid biopsy detection, capable of sensing GNAQ Q209P in plasma samples with a low ctDNA concentration and fractional abundance. Finally, our method was validated using plasma samples from metastatic UM patients.
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Subunidades alfa de la Proteína de Unión al GTP Gq-G11 , Subunidades alfa de la Proteína de Unión al GTP , Humanos , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Subunidades alfa de la Proteína de Unión al GTP/genética , Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Sistemas CRISPR-Cas/genética , MutaciónRESUMEN
The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex is one of the most remarkably altered epigenetic regulators in cancer. Pathogenic mutations in genes encoding SWI/SNF-related proteins have been recently described in many solid tumors, including rare and aggressive malignancies with rhabdoid features with no standard therapies in advanced or metastatic settings. In recent years, clinical trials with targeted drugs aimed at restoring its function have shown discouraging results. However, preclinical data have found an association between these epigenetic alterations and response to immune therapy. Thus, the rationale for immunotherapy strategies in SWI/SNF complex alteration-related tumors is strong. Here, we review the SWI/SNF complex and how its dysfunction drives the oncogenesis of rhabdoid tumors and the proposed strategies to revert this alteration and promising novel therapeutic approaches, including immune checkpoint inhibition and adoptive cell therapy.
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Proteínas de Unión al ADN , Tumor Rabdoide , Humanos , Proteínas de Unión al ADN/genética , Inmunoterapia Adoptiva , Proteínas Nucleares/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Tumor Rabdoide/genética , Tumor Rabdoide/terapia , Tumor Rabdoide/patologíaRESUMEN
Despite recent advances, treatment options for men with metastatic castration-resistant prostate cancer (mCRPC) progressing after next-generation hormonal agents (NHAs) are limited and provide only modest survival benefit. Thus, an unmet need remains for mCRPC patients after treatment with targeted endocrine therapy or NHA therapy. Pembrolizumab, a humanized monoclonal antibody for PD-1, has been found to have activity as monotherapy in patients with mCRPC and as combination therapy in a Phase Ib/II study with docetaxel and prednisone/prednisolone for patients previously treated with enzalutamide or abiraterone acetate. The aim of the randomized, double-blind, Phase III KEYNOTE-921 study is to evaluate the efficacy and safety of pembrolizumab plus docetaxel in patients with mCRPC who were previously treated with an NHA. Clinical trial registration: NCT03834506 (ClinicalTrials.gov).
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Docetaxel/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos Fase III como Asunto , Docetaxel/efectos adversos , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Prednisolona/administración & dosificación , Prednisolona/efectos adversos , Prednisona/administración & dosificación , Prednisona/efectos adversos , Supervivencia sin Progresión , Próstata/diagnóstico por imagen , Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: The main objective was to describe metastatic and survival rates in patients with small choroidal melanocytic lesions initially managed by observation. METHODS: Retrospective, observational study of consecutive cases recruited from 2001 through 2018, followed for a median (mean, range) of 81.0 (89.3, 10-204) months in a tertiary referral centre for ocular oncology. Seventy-five consecutive patients diagnosed with small choroidal melanocytic lesions with risk factors for growth initially observed and who showed progression during follow-up. Treatment was performed (plaque radiotherapy or enucleation in 96% and 4% of cases, respectively) at detection of tumour growth. RESULTS: Median (mean, range) tumour thickness was 2.2 (2.23, 1.08-3.40) mm, and median maximum basal diameter was 8.5 (8.16, 4-12) mm. At diagnosis, a median (mean, range) of 5 (5.48, 1-8) risk factors for progression were present. Lesions grew at a median (mean, range) rate of 0.42 mm/y (1.12, 0-7.68) in thickness and 1.05 mm/y (3.14, 0-4.8) in maximum diameter. Median (mean, range) time until growth was 17.00 (32.6, 1-161) months post-diagnosis, at which time tumours were treated. Five patients developed local recurrence after brachytherapy requiring enucleation. Four patients developed hepatic metastasis. Melanoma-specific survival was 98% at 5 years (95% CI, 94.2-100%) and 91.6% (95% CI, 82-100%) at 10 and 15 years. CONCLUSION: In small melanocytic lesions with risk factors for growth, initial observation until detection of tumour growth results in a seemingly low risk of metastasis, suggesting that this may be an initial approach to consider in tumours with indeterminate malignant potential.
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Braquiterapia , Neoplasias de la Coroides , Melanoma , Neoplasias de la Coroides/diagnóstico , Neoplasias de la Coroides/terapia , Humanos , Melanoma/diagnóstico , Melanoma/terapia , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Uveal melanoma (UM) is a malignant tumor that arises in the melanocytes of the uveal tract. It is the most frequent eye cancer, and despite new therapeutic approaches, prognosis is still poor, with up to 50% of patients developing metastasis with no efficient treatment options available. In contrast to cutaneous melanoma, UM is considered an "immune-cold" tumor due to the low mutational burden and the unique immunosuppressive microenvironment. To gain insight into the role of the UM microenvironment in regard to prognosis and metastatic progression, we have performed a pool analysis characterizing the UM microenvironment by using a bioinformatic approach. A variety of scores based on gene expression measuring stromal infiltration were calculated and used to assess association with prognosis. As a result, the highest immune and stromal scores were associated with poor prognosis. Specifically, stromal cells (fibroblasts and endothelial cells), T cells CD8+, natural killer (NK) cells, and macrophages M1 and M2 infiltration were associated with poor prognosis. Contrary to other tumors, lymphocytic infiltration is related to poor prognosis. Only B cells were associated with more favorable prognosis. UM samples scoring high in both angiogenesis (Angio) and antigen presentation (AP) pathways showed a poor prognosis suggesting an additive role of both functions. Almost all these tumors exhibited a chromosome 3 monosomy. Finally, an enrichment analysis showed that tumors classified as high Angio-high AP also activated metabolic pathways such as glycolysis or PI3K-AKT-MTOR. In summary, our pool analysis identified a cluster of samples with angiogenic and inflammatory phenotypes exhibiting poor prognosis and metabolic activation. Our analysis showed robust results replicated in a pool analysis merging different datasets from different analytic platforms.
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Linfocitos Infiltrantes de Tumor/patología , Melanoma/patología , Neovascularización Patológica/fisiopatología , Neoplasias de la Úvea/patología , Anciano , Animales , Presentación de Antígeno , Análisis por Conglomerados , Conjuntos de Datos como Asunto , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia , Estimación de Kaplan-Meier , Subgrupos Linfocitarios/patología , Macrófagos/patología , Masculino , Melanoma/irrigación sanguínea , Melanoma/genética , Melanoma/inmunología , Redes y Vías Metabólicas , Persona de Mediana Edad , Neovascularización Patológica/genética , Pronóstico , Transducción de Señal , Células del Estroma/patología , Microambiente Tumoral , Neoplasias de la Úvea/irrigación sanguínea , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/inmunologíaRESUMEN
PURPOSE: Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study. METHODS: POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case-control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation. RESULTS: Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies <1%, were identified. One ED variant (POLE p.Met294Arg) was classified as likely pathogenic, four as likely benign, and seven as variants of unknown significance. The most commonly associated tumor types were colorectal, endometrial and ovarian cancers. Loss-of-function and outside-ED variants are likely not pathogenic for this syndrome. CONCLUSIONS: Polymerase proofreading-associated syndrome constitutes 0.1-0.4% of familial cancer cases, reaching 0.3-0.7% when only CRC and polyposis are considered. ED variant interpretation is challenging and should include multiple pieces of evidence.
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Neoplasias Colorrectales , ADN Polimerasa II , ADN Polimerasa II/genética , ADN Polimerasa III , Mutación de Línea Germinal , Humanos , Mutación , Proteínas de Unión a Poli-ADP-Ribosa/genéticaRESUMEN
Immune checkpoint inhibitors (ICIs) are associated with various neurological adverse events (NAEs). We herein explored the incidence and clinical phenotype of immune-related NAEs in cancer patients. Medical records of ICI-treated cancer patients were reviewed between the years 2010 and 2018, with an aim to characterize immuno-related NAEs. A total of 1185 ICIs-treated patients were identified, 63.7% of which were males and 36.3% were females, with a mean age of 63.4 ± 7.3 years. Twenty-four from the overall ICIs-treated patients (2%) developed NAEs. No differences were identified in terms of age, sex, tumor type and class of ICIs between the patients who developed NAEs and those who did not. The median number of cycles of ICI treatment before NAEs onset were 4.5 (1-10), and the median time was 102 days. Peripheral nervous system (PNS) involvement was present in 14 patients (58.4%) and central nervous system (CNS) involvement in 10 (33.3%), including 2 patients with aseptic meningitis and polyradicular involvement. Amongst PNS complications, there were five (20.8%) with axonal sensory neuropathies, four (16.7%) with Guillain-Barre-like syndromes, and four (16.7%) with myositis and/or myasthenic syndromes. The majority of patients with PNS-related NAEs (n = 11; 78.6%) improved after ICIs discontinuation and treatment with immune-modulating therapies. The time to neuromuscular toxicities onset was significantly shorter, compared to CNS NAEs (median 70 vs 119 days, P = .037). Immune-related NAEs mostly present with neuromuscular complications. Discontinuation of ICIs and appropriate treatment should be commenced early throughout the process, in order to maximize a favorable outcome.
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Antineoplásicos Inmunológicos/toxicidad , Enfermedades del Sistema Nervioso Central/fisiopatología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/fisiopatología , Inhibidores de Puntos de Control Inmunológico/toxicidad , Neoplasias/tratamiento farmacológico , Enfermedades Neuromusculares/fisiopatología , Síndromes de Neurotoxicidad/fisiopatología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Anciano , Antineoplásicos Inmunológicos/administración & dosificación , Enfermedades del Sistema Nervioso Central/inducido químicamente , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/epidemiología , Ensayos Clínicos como Asunto , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Factores Inmunológicos/farmacología , Incidencia , Masculino , Persona de Mediana Edad , Enfermedades Neuromusculares/inducido químicamente , Enfermedades Neuromusculares/tratamiento farmacológico , Enfermedades Neuromusculares/epidemiología , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/epidemiología , Síndromes de Neurotoxicidad/etiología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/epidemiologíaRESUMEN
Due to the anatomical continuity of the uterine cavity with the cervix, genomic exploitation of material from routine Pap smears and other noninvasive sampling methods represent a unique opportunity to detect signs of disease using biological material shed from the upper genital tract. Recent research findings offer a promising perspective in the detection of endometrial cancer, but certain questions need to be addressed in order to accelerate the implementation of novel technologies in a routine screening or clinical setting. We discuss here new perspectives on detection of endometrial cancer using genomic and other biomarkers in minimally invasive sampling methods with a special focus on public health classic screening criteria, highlighting current gaps in knowledge.
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Neoplasias Endometriales/diagnóstico , Biomarcadores de Tumor/genética , Detección Precoz del Cáncer/métodos , Neoplasias Endometriales/genética , Femenino , Humanos , Tamizaje Masivo/métodosRESUMEN
Endometrial carcinoma is the most common cancer of the female genital tract. This review article discusses the usefulness of molecular techniques to classify endometrial carcinoma. Any proposal for molecular classification of neoplasms should integrate morphological features of the tumors. For that reason, we start with the current histological classification of endometrial carcinoma, by discussing the correlation between genotype and phenotype, and the most significant recent improvements. Then, we comment on some of the possible flaws of this classification, by discussing also the value of molecular pathology in improving them, including interobserver variation in pathologic interpretation of high grade tumors. Third, we discuss the importance of applying TCGA molecular approach to clinical practice. We also comment on the impact of intratumor heterogeneity in classification, and finally, we will discuss briefly, the usefulness of TCGA classification in tailoring immunotherapy in endometrial cancer patients. We suggest combining pathologic classification and the surrogate TCGA molecular classification for high-grade endometrial carcinomas, as an option to improve assessment of prognosis.
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Carcinoma Endometrioide/clasificación , ADN de Neoplasias/genética , Neoplasias Endometriales/clasificación , Inestabilidad de Microsatélites , Neoplasias Quísticas, Mucinosas y Serosas/clasificación , Tumores Neuroendocrinos/clasificación , Cadherinas/genética , Carcinoma Endometrioide/tratamiento farmacológico , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patología , Fosfatidilinositol 3-Quinasa Clase I , ADN Polimerasa II/genética , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Humanos , Mutación , Clasificación del Tumor , Neoplasias Quísticas, Mucinosas y Serosas/tratamiento farmacológico , Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Quísticas, Mucinosas y Serosas/patología , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Fosfohidrolasa PTEN/genética , Fenotipo , Fosfatidilinositol 3-Quinasas/genética , Proteínas de Unión a Poli-ADP-Ribosa , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína p53 Supresora de Tumor/genética , beta Catenina/genéticaRESUMEN
There have been no major improvements in the overall survival of ovarian cancer patients in recent decades. Even though more accurate surgery and more effective treatments are available, the mortality rate remains high. Given the differences in origin and the heterogeneity of these tumors, research to elucidate the signaling pathways involved is required. The Transforming Growth Factor (TGFß) family controls different cellular responses in development and cell homeostasis. Disruption of TGFß signaling has been implicated in many cancers, including ovarian cancer. This article considers the involvement of TGFß in ovarian cancer progression, and reviews the various mechanisms that enable the TGFß signaling pathway to control ovarian cancer cell proliferation. These mechanistic explanations support the therapeutic use of TGFß inhibitors in ovarian cancer, which are currently in the early phases of development.
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Proliferación Celular , Proteínas de Neoplasias/metabolismo , Neoplasias Ováricas/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Animales , Femenino , Humanos , Proteínas de Neoplasias/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Factor de Crecimiento Transformador beta/genéticaRESUMEN
BACKGROUND: Antibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized. METHODS: Fifty-eight patients with stage IV uveal melanoma received PD-1 or PD-1 ligand (PD-L1) antibodies between 2009 and 2015 at 9 academic centers. Patients who were evaluable for response were eligible for the analysis. Imaging was performed every 12 weeks and at the investigators' discretion. Safety and clinical efficacy outcomes, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively determined. RESULTS: Of 56 eligible patients, 48 (86%) had received prior therapy, and 35 (63%) had received treatment with ipilimumab. Three patients had an objective response to ipilimumab, and 8 had stable disease as their best response. Thirty-eight patients (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in 2 patients for an overall response rate of 3.6% (95% confidence interval [CI], 1.8%-22.5%). Stable disease (≥6 months) was observed in 5 patients (9%). The median PFS was 2.6 months (95% CI, 2.4-2.8 months), and the median OS was 7.6 months (95% CI, 0.7-14.6 months). There was no association between prior treatment with ipilimumab or liver-directed therapy and PFS or OS. Treatment was well tolerated, and only 1 patient discontinued treatment because of toxicity. CONCLUSIONS: PD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population. Cancer 2016;122:3344-3353. © 2016 American Cancer Society.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/inmunología , Melanoma/patología , Membrana Mucosa/patología , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias de la Úvea/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Persona de Mediana Edad , Membrana Mucosa/efectos de los fármacos , Estadificación de Neoplasias , Nivolumab , Pronóstico , Estudios Retrospectivos , Neoplasias Cutáneas , Tasa de Supervivencia , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/inmunología , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy. METHODS: In this double-blind study, we randomly assigned 1088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was unblinded after a planned interim analysis that was performed after 43% of the expected deaths had occurred. The median radiographic progression-free survival was 16.5 months with abiraterone-prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone-prednisone (median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the efficacy boundary. Abiraterone-prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more common with abiraterone-prednisone. CONCLUSIONS: Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer. (Funded by Janssen Research and Development, formerly Cougar Biotechnology; ClinicalTrials.gov number, NCT00887198.).
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Androstadienos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Prednisona/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Acetato de Abiraterona , Androstadienos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Método Doble Ciego , Humanos , Masculino , Metástasis de la Neoplasia , Prednisona/efectos adversos , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/secundario , Análisis de SupervivenciaRESUMEN
PURPOSE: To evaluate the efficacy of intravitreal dexamethasone implant 0.7 mg (Ozurdex) in radiation maculopathy secondary to plaque brachytherapy in choroidal melanoma. METHODS: Twelve eyes diagnosed of radiation maculopathy secondary to plaque brachytherapy and treated with intravitreal dexamethasone implant were included. Visual acuity, foveal thickness using spectral domain optical coherence tomography, and grade of macular edema, using Horgan classification, were evaluated. RESULTS: Mean age was 65.5 ± 28 years (range, 40-82 years). Mean follow-up was 8.2 ± 7.8 months (range, 2-28 months). Mean visual acuity before treatment was, in logarithm of the minimum angle of resolution scale, 1 ± 0.58 (range, 0.4-2) and mean final visual acuity 0.8 ± 0.58 (range, 0.2-2), showing a nonsignificant trend to improvement (P = 0.091; Wilcoxon's test). Foveal thickness before treatment was 416 ± 263 µm (range, 222-725 µm) and final foveal thickness 254 ± 170 µm (range, 145-750), showing a significant decrease (P = 0.016; Wilcoxon's test). Referring to Horgan classification, a significant reduction in grades before and after treatment was demonstrated (P = 0.007; Wilcoxon's test). CONCLUSION: Ozurdex is a useful treatment for radiation maculopathy associated to plaque brachytherapy for uveal melanoma, with a significant decrease in foveal thickness and a significant improvement in Horgan classification. This anatomical improvement was correlated with a moderate improvement in visual acuity.
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Braquiterapia/efectos adversos , Neoplasias de la Coroides/radioterapia , Dexametasona/administración & dosificación , Glucocorticoides/administración & dosificación , Melanoma/radioterapia , Traumatismos por Radiación/tratamiento farmacológico , Retina/efectos de la radiación , Adulto , Anciano , Anciano de 80 o más Años , Implantes de Medicamentos , Femenino , Angiografía con Fluoresceína , Humanos , Inyecciones Intravítreas , Radioisótopos de Yodo/efectos adversos , Masculino , Persona de Mediana Edad , Traumatismos por Radiación/etiología , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/etiología , Radioisótopos de Rutenio/efectos adversos , Tomografía de Coherencia Óptica , Agudeza VisualRESUMEN
Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune checkpoint (IC) ligand profile according to their features, dictating the IC pathways involved in immune evasion. Epithelial cancer cells, through the PD-1/PD-L1 pathway, and mesenchymal cancer cells, through the CTLA-4/CD80 and TIGIT/CD155 pathways, differentially block antitumor immune responses and determine the response to ICB therapies. Accordingly, the anti-PD-L1/TIGIT combination is the most effective strategy for blocking the growth of cSCCs that contain both epithelial and mesenchymal cancer cells. The expression of E-cadherin/Vimentin/CD80/CD155 proteins in cSCC, HNSCC and melanoma patient samples predicts response to anti-PD-1/PD-L1 therapy. Collectively, our findings indicate that the selection of ICB therapies should take into account the epithelial/mesenchymal features of cancer cells.
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Antígeno B7-H1 , Carcinoma de Células Escamosas , Plasticidad de la Célula , Transición Epitelial-Mesenquimal , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias Cutáneas , Animales , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/tratamiento farmacológico , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Ratones , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Masculino , Inmunoterapia/métodos , Transición Epitelial-Mesenquimal/inmunología , Plasticidad de la Célula/efectos de los fármacos , Línea Celular Tumoral , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/inmunología , Receptores Virales/metabolismo , Receptores Virales/genética , Antígeno B7-1/metabolismo , Receptores Inmunológicos/metabolismoRESUMEN
BACKGROUND: Tebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with 1-year OS of 62% in the primary analysis of study IMCgp100-102. Here we report long-term outcomes from this phase 1/2 study in pretreated mUM. PATIENTS AND METHODS: Patients with previously treated mUM received tebentafusp weekly intravenous at 20 µg dose 1, 30 µg dose 2 and either 54, 64, 68, or 73 µg (phase 1) or 68 µg (phase 2) dose 3+. The primary objective was overall response rate. Secondary objectives included OS and safety. OS was estimated by Kaplan-Meier methods. Association between OS and baseline covariates, on-treatment Response Evaluation Criteria in Solid Tumors (RECIST) response, baseline tumor biopsy and circulating-tumor DNA (ctDNA) changes were assessed. RESULTS: 146 patients were treated with tebentafusp: 19 in phase 1 and 127 in phase 2. With a median follow-up duration of 48.5 months, the median OS was 17.4 months (95% CI, 13.1 to 22.8), and the 1-year, 2-year, 3-year and 4-year OS rates were 62%, 40%, 23% and 14%, respectively. Improved survival was associated with lower ctDNA baseline levels and greater ctDNA reductions by week 9 on-treatment, with 100% 1-year, 73% 2-year and 45% 3-year OS rates for patients with ctDNA clearance. Baseline gp100 expression was not associated with survival, despite more RECIST responses among patients with higher expression. No new safety signals were reported with long-term dosing. CONCLUSIONS: This study represents the longest follow-up of a Tcell receptor bispecific to date and confirms the durable survival benefits achieved with tebentafusp in previously treated mUM with good tolerability long-term. A role for ctDNA reduction as an early indicator of clinical benefit was again suggested for patients treated with tebentafusp.
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Melanoma , Neoplasias de la Úvea , Humanos , Melanoma/tratamiento farmacológico , Melanoma/mortalidad , Melanoma/patología , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/mortalidad , Neoplasias de la Úvea/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Estudios de Seguimiento , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/farmacología , Anciano de 80 o más Años , Metástasis de la NeoplasiaRESUMEN
Uveal melanoma (UM) is an ocular cancer, with propensity for lethal liver metastases. When metastatic UM (MUM) occurs, as few as 8% of patients survive beyond two years. Efficacious treatments for MUM are urgently needed. 1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT1) antagonist, alters UM cancer hallmarks in vitro, ex vivo and in vivo. Here, we investigated the 1,4-dihydroxy quininib mechanism of action and its translational potential in MUM. Proteomic profiling of OMM2.5 cells identified proteins differentially expressed after 1,4-dihydroxy quininib treatment. Glutathione peroxidase 4 (GPX4), glutamate-cysteine ligase modifier subunit (GCLM), heme oxygenase 1 (HO-1) and 4 hydroxynonenal (4-HNE) expression were assessed by immunoblots. Biliverdin, glutathione and lipid hydroperoxide were measured biochemically. Association between the expression of a specific ferroptosis signature and UM patient survival was performed using public databases. Our data revealed that 1,4-dihydroxy quininib modulates the expression of ferroptosis markers in OMM2.5 cells. Biochemical assays validated that GPX4, biliverdin, GCLM, glutathione and lipid hydroperoxide were significantly altered. HO-1 and 4-HNE levels were significantly increased in MUM tumor explants from orthotopic patient-derived xenografts (OPDX). Expression of genes inhibiting ferroptosis is significantly increased in UM patients with chromosome 3 monosomy. We identified IFerr, a novel ferroptosis signature correlating with UM patient survival. Altogether, we demontrated that in MUM cells and tissues, 1,4-dihydroxy quininib modulates key markers that induce ferroptosis, a relatively new type of cell death driven by iron-dependent peroxidation of phospholipids. Furthermore, we showed that high expression of specific genes inhibiting ferroptosis is associated with a worse UM prognosis, thus, the IFerr signature is a potential prognosticator for which patients develop MUM. All in all, ferroptosis has potential as a clinical biomarker and therapeutic target for MUM.