RESUMEN
BACKGROUND: A lack of onsite clinical trials is the largest barrier to participation of cancer patients in trials. Development of an automated process for regional trial eligibility screening first requires identification of patient electronic health record data that allows effective trial screening, and evidence that searching for trials regionally has a positive impact compared with site-specific searching. METHODS: To assess a screening framework that would support an automated regional search tool, a set of patient clinical variables was analyzed for prescreening clinical trials. The variables were used to assess regional compared with site-specific screening throughout the United States. RESULTS: Eight core variables from patient electronic health records were identified that yielded likely matches in a prescreen process. Assessment of the screening framework was performed using these variables to search for trials locally and regionally for an 84-patient cohort. The likelihood that a trial returned in this prescreen was a provisional trial match was 45.7%. Expanding the search radius to 20 miles led to a net 91% increase in matches across cancers within the tested cohort. In a U.S. regional analysis, for sparsely populated areas, searching a 100-mile radius using the prescreening framework was needed, whereas for urban areas a 20-mile radius was sufficient. CONCLUSION: A clinical trial screening framework was assessed that uses limited patient data to efficiently and effectively identify prescreen matches for clinical trials. This framework improves trial matching rates when searching regionally compared with locally, although the applicability of this framework may vary geographically depending on oncology practice density. PLAIN LANGUAGE SUMMARY: Clinical trials provide cancer patients the opportunity to participate in research and development of new drugs and treatment approaches. It can be difficult to find available clinical trials for which a patient is eligible. This article describes an approach to clinical trial matching using limited patient data to search for trials regionally, beyond just the patient's local care site. Feasibility testing shows that this process can lead to a net 91% increase in the number of potential clinical trial matches available within 20 miles of a patient. Based on these findings, a software tool based on this model is being developed that will automatically send limited, deidentified information from patient medical records to services that can identify possible clinical trials within a given region.
Asunto(s)
Neoplasias , Humanos , Registros Electrónicos de Salud , Determinación de la Elegibilidad , Estudios de Factibilidad , Neoplasias/diagnóstico , Neoplasias/terapia , Selección de Paciente , Ensayos Clínicos como AsuntoRESUMEN
Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL for nearly 60% of individuals with classical CdLS, and by mutations in the core cohesin components SMC1A (~5%) and SMC3 (<1%) for a smaller fraction of probands. In humans, the multisubunit complex cohesin is made up of SMC1, SMC3, RAD21 and a STAG protein. These form a ring structure that is proposed to encircle sister chromatids to mediate sister chromatid cohesion and also has key roles in gene regulation. SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin, and in yeast, the class I histone deacetylase Hos1 deacetylates SMC3 during anaphase. Here we identify HDAC8 as the vertebrate SMC3 deacetylase, as well as loss-of-function HDAC8 mutations in six CdLS probands. Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the 'used' cohesin complex released from chromatin in both prophase and anaphase. SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/metabolismo , Histona Desacetilasas/genética , Mutación/genética , Proteínas Represoras/genética , Acetilación , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Anafase , Sitios de Unión , Proteínas de Ciclo Celular/química , Proteoglicanos Tipo Condroitín Sulfato/química , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Cromatina/genética , Cromatina/metabolismo , Inmunoprecipitación de Cromatina , Proteínas Cromosómicas no Histona/química , Cristalografía por Rayos X , Proteínas de Unión al ADN , Femenino , Fibroblastos , Células HeLa , Histona Desacetilasas/química , Histona Desacetilasas/deficiencia , Histona Desacetilasas/metabolismo , Humanos , Masculino , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Profase , Conformación Proteica , Proteínas/genética , Proteínas Represoras/química , Proteínas Represoras/deficiencia , Proteínas Represoras/metabolismo , Transcripción Genética , CohesinasRESUMEN
Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for â¼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.
Asunto(s)
Fontanelas Craneales/anomalías , Síndrome de Cornelia de Lange/enzimología , Anomalías del Ojo/enzimología , Genes Ligados a X , Histona Desacetilasas/genética , Hipertelorismo/enzimología , Proteínas Represoras/genética , Secuencia de Aminoácidos , Niño , Preescolar , Estudios de Cohortes , Fontanelas Craneales/enzimología , Síndrome de Cornelia de Lange/genética , Anomalías del Ojo/genética , Femenino , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Hipertelorismo/genética , Lactante , Masculino , Datos de Secuencia Molecular , Mutación Missense , Fenotipo , Proteínas Represoras/química , Proteínas Represoras/metabolismo , Alineación de SecuenciaRESUMEN
PURPOSE: Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder characterized by mental retardation, limb abnormalities, distinctive facial features, and hirsutism. Mutations in three genes involved in sister chromatid cohesion, NIPBL, SMC1A, and SMC3, account for ~55% of CdLS cases. The molecular etiology of a significant fraction of CdLS cases remains unknown. We hypothesized that large genomic rearrangements of cohesin complex subunit genes may play a role in the molecular etiology of this disorder. METHODS: Custom high-resolution oligonucleotide array comparative genomic hybridization analyses interrogating candidate cohesin genes and breakpoint junction sequencing of identified genomic variants were performed. RESULTS: Of the 162 patients with CdLS, for whom mutations in known CdLS genes were previously negative by sequencing, deletions containing NIPBL exons were observed in 7 subjects (~5%). Breakpoint sequences in five patients implicated microhomology-mediated replicative mechanisms-such as serial replication slippage and fork stalling and template switching/microhomology-mediated break-induced replication-as a potential predominant contributor to these copy number variations. Most deletions are predicted to result in haploinsufficiency due to heterozygous loss-of-function mutations; such mutations may result in a more severe CdLS phenotype. CONCLUSION: Our findings suggest a potential clinical utility to testing for copy number variations involving NIPBL when clinically diagnosed CdLS cases are mutation-negative by DNA-sequencing studies.
Asunto(s)
Replicación del ADN , Síndrome de Cornelia de Lange/genética , Estudios de Asociación Genética , Proteínas/genética , Recombinación Genética , Adolescente , Secuencia de Bases , Proteínas de Ciclo Celular , Niño , Preescolar , Puntos de Rotura del Cromosoma , Hibridación Genómica Comparativa , Facies , Femenino , Eliminación de Gen , Orden Génico , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Fenotipo , Alineación de SecuenciaRESUMEN
BACKGROUND: Preclinical breast cancer models with acquired HER2 resistance exhibit decreased proliferation with CDK4/6 inhibition in tumors with intact Rb and low p16 levels. Adding cytotoxic agents like T-DM1 enhances the inhibitory CDK4/6 cytostatic effect. PATIENTS AND METHODS: A phase I/Ib 3+3 dose escalation/expansion trial of palbociclib and T-DM1 identified 150 mg on days 5 to 18 as the palbociclib maximal tolerated dose combined with day 1 intravenous T-DM1 in 21-day treatment cycles. Patients were previously treated with trastuzumab and a taxane with no limitation on prior therapy lines, including prior pertuzumab, lapitinib, neratinib, and T-DM1. Median age was 54 years and two-thirds were estrogen receptor positive. Primary objectives included maximum tolerated dose as determined by dose-limiting toxicity, and secondary end points of safety, toxicity, response rate, response duration, and progression-free survival. RESULTS: From May 2014 to August 2018, 18 total patients were treated. The median number of cycles was 6.5 (1-22). A maximum tolerated dose was not reached. The most common G3 toxicity of more than 10% incidence was hematologic. Overall response rate (complete response + partial response) was 33% (95% confidence interval, 13%-59%). Median duration of response in responders was not reached and median-progression free survival was 6 months (95% confidence interval, 2.5-11.6). CONCLUSIONS: The combination of day 1 T-DM1 and days 5 to 18 palbociclib is safe, tolerable, and active in previously treated HER2-positive relapsed patients. Observed hematologic toxicity is manageable. The trial response rate confirms that a CDK 4/6 inhibitor can resensitize HER2-resistant breast cancer.
Asunto(s)
Ado-Trastuzumab Emtansina/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Piperazinas/uso terapéutico , Piridinas/uso terapéutico , Taxoides/uso terapéutico , Trastuzumab/uso terapéutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Femenino , Humanos , Dosis Máxima Tolerada , Persona de Mediana EdadRESUMEN
IMPORTANCE: As cancer treatment has become more individualized, oncologic clinical trials have become more complex. Increasingly numerous and stringent eligibility criteria frequently include tumor molecular or genomic characteristics that may not be readily identified in medical records, rendering it difficult to best match clinical trials with clinical sites and to identify potentially eligible patients once a clinical trial has been selected and activated. Partly because of these factors, enrollment rates for cancer clinical trials remain low, creating delays and increased costs for drug development. Information technology (IT) platforms have been applied to the implementation and conduct of clinical trials to improve efficiencies in several medical fields, and these platforms have recently been introduced to oncologic studies. OBSERVATIONS: This review summarizes cancer and noncancer studies that used IT platforms for assistance with clinical trial site selection, patient recruitment, and patient screening. The review does not address the use of IT in other aspects of clinical research, such as wearable physical activity monitors or telehealth visits. A large number of IT platforms (which may be patient facing, site or investigator facing, or sponsor facing) are now commercially available. These applications use artificial intelligence and/or natural language processing to identify and summarize protocol eligibility criteria, institutional patient populations, and individual electronic health records. Although there is an expanding body of literature examining the role of this technology, relatively few studies to date have been performed in oncologic settings. CONCLUSIONS AND RELEVANCE: This review found that an increasing number and variety of IT platforms were available to assist in the planning and conduct of clinical trials. Because oncologic clinical care and clinical trial protocols are particularly complex, nuanced, and individualized, published experience with this technology in other fields may not be fully applicable to cancer settings. The extent to which these services will overcome ongoing and increasing challenges in cancer clinical research remains unclear.
Asunto(s)
Tecnología de la Información , Neoplasias , Inteligencia Artificial , Humanos , Procesamiento de Lenguaje Natural , Neoplasias/tratamiento farmacológico , Selección de PacienteRESUMEN
BACKGROUND: Proof of the clinical utility of a biomarker is when its use informs a management decision and improves patient outcomes relative to when it is not used. OBJECTIVE: To model the clinical benefit of the nuclear-localized androgen receptor splice variant 7 (AR-V7) test for men with progressing metastatic castration-resistant prostate cancer (mCRPC) at the second line of therapy or greater to inform the choice of an androgen receptor signaling inhibitor (ARSI) or a taxane. DESIGN, SETTING, AND PARTICIPANTS: The study population was a cross-sectional cohort of 193 unique patients with progressing mCRPC from whom 255 samples were drawn at the time of the second line or later treatment decision who then received an ARSI or taxane, with up to 3â¯yr of additional follow-up Circulating tumor cells (CTCs) were identified from blood samples and tested for AR-V7. Physicians were blinded to AR-V7 status and the testing laboratory was blinded to outcomes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: We measured physician propensity for choosing an ARSI or taxane based on patient prognosis. We also measured overall survival (OS) adjusted for physician propensity by drug class; OS data were analyzed both without and with knowledge of nuclear-localized AR-V7 status. RESULTS AND LIMITATIONS: Treating physicians had a propensity for choosing a taxane over an ARSI for patients with more advanced disease or who received an ARSI as the immediate prior therapy. After adjusting for physician propensity, discernible OS differences were not observed between taxane- and ARSI-treated patients (median 15.6 vs 14.4 mo; pâ¯=0.11). Patients with detectable nuclear-localized AR-V7 in CTCs had superior survival with taxanes over ARSIs (median 9.8 vs 5.7 mo; pâ¯=â¯0.041). AR-V7-negative patients had superior survival on ARSIs over taxanes (pâ¯=â¯0.033) but overlapping curves limit the interpretation. Mutivariable models showed a robust interaction between AR-V7 status and drug, and a lower risk of death on taxanes for AR-V7-positive men. CONCLUSIONS: Use of the nuclear-localized AR-V7 CTC test to inform treatment choice can improve patient outcomes relative to decisions based solely on standard-of-care measures. PATIENT SUMMARY: Men with metastatic prostate cancer who test positive for AR-V7 protein in circulating tumor cells are likely to live longer if taxane chemotherapy is used.
Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Biomarcadores de Tumor/sangre , Células Neoplásicas Circulantes , Neoplasias de la Próstata Resistentes a la Castración/sangre , Receptores Androgénicos/sangre , Taxoides/uso terapéutico , Anciano , Núcleo Celular , Estudios Transversales , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Isoformas de Proteínas/sangre , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Chromosomal instability (CIN) increases a tumor cell's ability to acquire chromosomal alterations, a mechanism by which tumor cells evolve, adapt, and resist therapeutics. We sought to develop a biomarker of CIN in circulating tumor cells (CTC) that are more likely to reflect the genetic diversity of patient's disease than a single-site biopsy and be assessed rapidly so as to inform treatment management decisions in real time. Large-scale transitions (LST) are genomic alterations defined as chromosomal breakages that generate chromosomal gains or losses of greater than or equal to10 Mb. Here we studied the relationship between the number of LST in an individual CTC determined by direct sequencing and morphologic features of the cells. This relationship was then used to develop a computer vision algorithm that utilizes CTC image features to predict the presence of a high (9 or more) versus low (8 or fewer) LST number in a single cell. As LSTs are a primary functional component of homologous recombination deficient cellular phenotypes, the image-based algorithm was studied prospectively on 10,240 CTCs in 367 blood samples obtained from 294 patients with progressing metastatic castration-resistant prostate cancer taken prior to starting a standard-of-care approved therapy. The resultant computer vision-based biomarker of CIN in CTCs in a pretreatment sample strongly associated with poor overall survival times in patients treated with androgen receptor signaling inhibitors and taxanes. SIGNIFICANCE: A rapidly assessable biomarker of chromosomal instability in CTC is associated with poor outcomes when detected in men with progressing mCRPC.
Asunto(s)
Algoritmos , Inestabilidad Cromosómica/genética , Células Neoplásicas Circulantes , Neoplasias de la Próstata Resistentes a la Castración/genética , Anciano , Anciano de 80 o más Años , Rotura Cromosómica , Variaciones en el Número de Copia de ADN , Progresión de la Enfermedad , Marcadores Genéticos , Variación Estructural del Genoma , Ensayos Analíticos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
PURPOSE: The genomic underpinning of clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer is unclear. EXPERIMENTAL DESIGN: In patients with metastatic castration-sensitive prostate cancer at a tertiary referral center, clinical-grade targeted tumor sequencing was performed to quantify tumor DNA copy number alterations and alterations in predefined oncogenic signaling pathways. Disease volume was classified as high volume (≥4 bone metastases or visceral metastases) versus low volume. RESULTS: Among 424 patients (88% white), 213 (50%) had high-volume disease and 211 (50%) had low-volume disease, 275 (65%) had de novo metastatic disease, and 149 (35%) had metastatic recurrence of nonmetastatic disease. Rates of castration resistance [adjusted hazard ratio, 1.84; 95% confidence interval (CI), 1.40-2.41] and death (adjusted hazard ratio, 3.71; 95% CI, 2.28-6.02) were higher in high-volume disease. Tumors from high-volume disease had more copy number alterations. The NOTCH, cell cycle, and epigenetic modifier pathways were the highest-ranking pathways enriched in high-volume disease. De novo metastatic disease differed from metastatic recurrences in the prevalence of CDK12 alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in AR, SPOP (inverse), and TP53, and the cell cycle, WNT (inverse), and MYC pathways, adjusting for disease volume and other genomic pathways. Overall survival rates differed 2-fold to 4-fold according to AR, SPOP (inverse), WNT (inverse), and cell-cycle alterations. PI3K pathway alterations were not associated with prognosis once adjusted for other factors. CONCLUSIONS: This study identified genomic features associated with prognosis in metastatic castration-sensitive disease that may aid in molecular classification and treatment selection.
Asunto(s)
Biomarcadores de Tumor , Variación Genética , Genómica , Oncogenes , Fenotipo , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Anciano , Resistencia a Antineoplásicos/genética , Genómica/métodos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Orquiectomía , Pronóstico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/terapia , Resultado del TratamientoRESUMEN
IMPORTANCE: The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown. OBJECTIVE: To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population. DESIGN, SETTING, AND PARTICIPANTS: In this case series, 1551 tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed using a targeted sequencing assay from January 1, 2015, through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. For each patient, clinical outcomes were reported, with follow-up until May 31, 2018. MAIN OUTCOMES AND MEASURES: Tumor mutation burden and MSIsensor score, a quantitative measure of MSI, were calculated. Mutational signature analysis and immunohistochemistry for MMR protein expression were performed in select cases. RESULTS: Among the 1033 patients who had adequate tumor quality for MSIsensor analysis (mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/dMMR patients (21.9%) had a pathogenic germline mutation in a Lynch syndrome-associated gene. Six patients had more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their disease course. Eleven patients with MSI-H/dMMR castration-resistant prostate cancer received anti-PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018, 5 of the 6 responders (5 of 11 total [45.5%]) were still on therapy for as long as 89 weeks. CONCLUSIONS AND RELEVANCE: The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti-PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/dMMR phenotype respond, further studies should explore mechanisms of resistance.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Reparación de la Incompatibilidad de ADN , Inestabilidad de Microsatélites , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Resultado del TratamientoRESUMEN
Cornelia de Lange syndrome (CdLS; or Brachmann-de Lange syndrome) is a dominantly inherited congenital malformation disorder with features that include characteristic facies, cognitive delays, growth retardation and limb anomalies. Mutations in nearly 60% of CdLS patients have been identified in NIPBL, which encodes a regulator of the sister chromatid cohesion complex. NIPBL, also known as delangin, is a homolog of yeast and amphibian Scc2 and C. elegans PQN-85. Although the exact mechanism of NIPBL function in sister chromatid cohesion is unclear, in vivo yeast and C. elegans experiments and in vitro vertebrate cell experiments have demonstrated that NIPBL/Scc2 functionally interacts with the MAU2/Scc4 protein to initiate loading of cohesin onto chromatin. To test the significance of this model in the clinical setting of CdLS, we fine-mapped the NIBPL-MAU2 interaction domain and tested the functional significance of missense mutations and variants in NIPBL and MAU2 identified in these minimal domains in a cohort of patients with CdLS. We demonstrate that specific novel mutations at the N-terminus of the MAU2-interacting domain of NIBPL result in markedly reduced MAU2 binding, although we appreciate no consistent clinical difference in the small group of patients with these mutations. These data suggest that factors in addition to MAU2 are essential in determining the clinical features and severity of CdLS.