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Immunotherapy is an important modality in the treatment of many types of malignancy. The optimal duration of treatment with immunotherapy in patients with metastatic malignancies who experience complete responses is not fully understood. Our case demonstrates a protracted complete response in a patient with metastatic gastric adenocarcinoma after just three doses of pembrolizumab. This illustrates a need for further research into which patients might have responses such as these and could therefore be spared additional doses of an expensive treatment with many potential side effects.
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INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a genetically heterogeneous disease often diagnosed with synchronous metastatic disease involving the liver. Tumors with extra-abdominal spread that bypass the liver are thought to represent a unique molecular subgroup and those with isolated pulmonary metastatic disease are thought to have a more favorable clinical phenotype. METHOD: We conducted a retrospective review of patients with pathologically confirmed PDAC treated between the years 2007 and 2020 at a Scripps Health hospital. The final study sample (N = 205) included patients with isolated pulmonary metastasis (IL), isolated liver metastasis or synchronous liver and lung metastasis (LL), or metastasis to any site other than the liver or lung (NLL). Primary endpoint was overall survival (OS). Progression-free survival (PFS) and recurrence-free survival (RFS) were analyzed as secondary endpoints. Each survival outcome was analyzed using Cox proportional hazards tests. RESULTS: No statistically significant differences were seen between the three groups in OS, PFS, or RFS. Median OS for the IL group was 561 days, 341 days for the LL group, and 441 days for the NLL group. Median RFS was 748 days for the IL group, 574 days for the LL group, and 545 days for the NLL group. Median PFS was 307 for the IL group, 236 for the LL group, and 265 for the NLL group. When comparing only the IL and LL groups, a statistically significant difference in OS was seen favoring the IL group (HR1.59 LL vs IL [ref], CI 1.04-2.41, p = 0.031) CONCLUSION: Though statistically significant differences in survival outcomes were not seen in our population, there was a trend toward improved survival for patients with isolated lung metastases. When comparing only the IL to LL group, statistically significant overall survival favoring the IL group was seen. These findings highlight a potential prognostic indicator of metastatic PDAC.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pulmonares , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patología , Adenocarcinoma/patología , Carcinoma Ductal Pancreático/patología , Pronóstico , Pulmón/patología , Estudios RetrospectivosRESUMEN
BACKGROUND: There is no agreed upon standard of care for borderline-resectable pancreatic cancer (BRPC) or locally-advanced pancreatic cancer (LAPC) patients regarding the benefit of chemotherapy or radiation alone or in combination. PATIENTS AND METHODS: We completed a retrospective cohort analysis of BRPC and LAPC patients at a cancer center with expertise in multi-disciplinary pancreatic ductal adenocarcinoma (PDAC) treatment over a 5-year period from 03/01/2014 to 03/01/2019 (cut-off date). The total evaluable newly diagnosed, treatment naïve, BRPC, and LAPC patients with adequate organ function and ability to obtain treatment after multidisciplinary review was 52 patients. After analysis, patients were evaluated for rates of resection, extent of resection (R0 or R1), median progression-free survival (mPFS), and median overall survival (mOS). RESULTS: Patients were treated with chemotherapy alone (gemcitabine and nab-paclitaxel = 77% (20/26); FOLFIRINOX = 19% (5/26); single agent gemcitabine 3.8% (1/26)), or chemotherapy followed by chemoradiation (gemcitabine +5 Gy × 5 weeks), or chemoradiation alone prior to re-staging and potential resection. Of the 29% (15/52) of patients who went on to surgical resection, 73% (11/15) achieved R0 resection. An R0 resection was achieved in 35% (9/26) of patients treated with chemotherapy alone, 7.6% (1/13) in a patient treated with chemotherapy followed by radiation, and 7.6% (1/13) with concurrent chemoradiotherapy alone. Chemotherapy alone achieved a mPFS of 16.4 months (p < 0.0025) and mOS of 26.2 months (p < 0.0001), chemotherapy followed by chemoradiation was 13.0 months and 14.9 months respectively, while concurrent chemoradiotherapy was 6.9 months and 7.3 months. CONCLUSIONS AND RELEVANCE: BRPC and LAPC patients capable of surgery after only receiving neoadjuvant treatment with chemotherapy had higher rates of R0 resection with prolonged median PFS and OS compared with any patient needing combination chemotherapy with radiotherapy.
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Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patología , Terapia Neoadyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Retrospectivos , Fluorouracilo , Leucovorina , Neoplasias PancreáticasRESUMEN
Mesenchymal colorectal cancer (mCRC) is microsatellite stable (MSS), highly desmoplastic, with CD8+ T cells excluded to the stromal periphery, resistant to immunotherapy, and driven by low levels of the atypical protein kinase Cs (aPKCs) in the intestinal epithelium. We show here that a salient feature of these tumors is the accumulation of hyaluronan (HA) which, along with reduced aPKC levels, predicts poor survival. HA promotes epithelial heterogeneity and the emergence of a tumor fetal metaplastic cell (TFMC) population endowed with invasive cancer features through a network of interactions with activated fibroblasts. TFMCs are sensitive to HA deposition, and their metaplastic markers have prognostic value. We demonstrate that in vivo HA degradation with a clinical dose of hyaluronidase impairs mCRC tumorigenesis and liver metastasis and enables immune checkpoint blockade therapy by promoting the recruitment of B and CD8+ T cells, including a proportion with resident memory features, and by blocking immunosuppression.
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Neoplasias Colorrectales , Ácido Hialurónico , Microambiente Tumoral , Humanos , Linfocitos T CD8-positivos/patología , Neoplasias Colorrectales/patología , Ácido Hialurónico/metabolismo , Inmunoterapia , Sarcoma/patología , Microambiente Tumoral/fisiologíaRESUMEN
Aim: To delineate clinical correlates of COVID-19 infection severity in hospitalized patients with malignancy. Methods: The authors conducted a retrospective review of all hospitalized patients with a hematologic and/or solid tumor malignancy presenting to the authors' institution between 1 March 2020 and 5 January 2021, with a laboratory confirmed diagnosis of COVID-19. Univariate and multivariate logistic regression analyses were used to determine associations between specific severity outcomes and clinical characteristics. Results: Among 2771 hospitalized patients with COVID-19, 246 (8.88%) met inclusion criteria. Patients who were actively receiving treatment had an increased rate of death following admission (odds ratio [OR]: 2.7). After adjusting for significant covariates, the odds ratio increased to 4.4. Patients with cancer involvement of the lungs had a trend toward increased odds of death after adjusting for covariates (OR: 2.3). Conclusions: Among COVID-19 positive hospitalized cancer patients, systemic anti-cancer therapy was associated with significantly increased odds of mortality.
Plain language summary Though cancer is a biologically heterogenous disease with a wide spectrum of clinical features and behavior, accumulating evidence suggests that cancer patients are at greater susceptibility to COVID-19 infection and more likely to experience morbidity and mortality from COVID-19 infection than non-cancer patients. In this study, the authors reviewed the clinical characteristics of patients with a diagnosis of cancer hospitalized with COVID-19 to assess potential correlates of COVID-19 severity in this population. Notably, analysis of the hospital data revealed a statistically significant increased incidence of mortality in cancer patients who were receiving systemic anti-cancer treatment, including chemotherapy, immunotherapy or targeted therapy, than in those not on therapy. Likewise, there was a trend toward increased mortality in those with either primary or metastatic tumor involvement of the lung compared with those without lung involvement.
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COVID-19/complicaciones , COVID-19/mortalidad , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , California/epidemiología , Femenino , Hospitalización , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Factores Inmunológicos/uso terapéutico , Neoplasias Pulmonares/complicaciones , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Gravedad del Paciente , Estudios Retrospectivos , SARS-CoV-2RESUMEN
Glycans, chains of sugar molecules found conjugated to cell proteins and lipids, contribute to their growth, movement and differentiation. Aberrant glycosylation is a hallmark of several medical conditions including tumorigenesis. Glycosphingolipids (GSLs), consisting of glycans conjugated to a lipid (ceramide) core, are found in the lipid bilayer of eukaryotic cell membranes. GSLs, play an active role in cell processes. Several GSLs are expressed by human embryonic stem cells and have been found to be overexpressed in several types of cancer. In this review, we discuss the data, hypotheses and perspectives related to the GSLs Globo H and SSEA-4.
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Antígenos de Carbohidratos Asociados a Tumores/fisiología , Neoplasias/etiología , Antígenos Embrionarios Específico de Estadio/fisiología , Antígenos de Carbohidratos Asociados a Tumores/inmunología , Vacunas contra el Cáncer/uso terapéutico , Desarrollo Embrionario , Glicoconjugados/fisiología , Glicoesfingolípidos/antagonistas & inhibidores , Glicoesfingolípidos/fisiología , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Antígenos Embrionarios Específico de Estadio/inmunologíaRESUMEN
Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a very rare neoplasm, with distinct epidemiologic, morphologic and clinical characteristics. Molecular mechanistic insight into the pathogenesis of this carcinoma suggests a pivotal role for the host immune system in the proliferation and progression of this tumor. However, while detailed genomic profiling of these hepatic tumors have revealed an intra-tumoral inflammatory mutational signature that may predispose to immune checkpoint inhibitor efficacy, no published report has described their use in this tumor type. Unfortunately, with near 100 cases of LEL-HCC reported in the literature to date and the majority of cases confined to localized and resectable disease, current evidence-based practices in the unresectable setting are lacking, with unknown benefit of chemotherapy or immunotherapy. We report on the case of a 68 year-old man with unresectable, advanced LEL-HCC who had evidence of disease stability after starting on the immune checkpoint inhibitor nivolumab. His disease response persisted off therapy for over a year and was potentially augmented by radiotherapy at the site of local progression. For this extremely rare tumor subtype, this case highlights the potential efficacy and safety of immune checkpoint blockade in LEL-HCC and reinforces the need for more robust, large-scale analysis of patients with these rare tumors to better evaluate treatment strategies and outcomes.
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PURPOSE: To evaluate the efficacy and safety of pegvorhyaluronidase alfa (PEGPH20) plus nab-paclitaxel/gemcitabine (AG) in patients with hyaluronan-high metastatic pancreatic ductal adenocarcinoma (PDA). PATIENTS AND METHODS: HALO 109-301 was a phase III, randomized, double-blind, placebo-controlled study. Patients ≥ 18 years of age with untreated, metastatic, hyaluronan-high PDA were randomly assigned 2:1 to PEGPH20 plus AG or placebo plus AG. Treatment was administered intravenously in 4-week cycles (3 weeks on, 1 week off) until progression or intolerable adverse events: PEGPH20 3.0 µg/kg twice per week for cycle 1 and once per week thereafter; nab-paclitaxel 125 mg/m2 once per week; and gemcitabine 1,000 mg/m2 once per week. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Response was independently assessed per RECIST v1.1. RESULTS: At data cutoff, 494 patients were randomly assigned, with 492 (327 for PEGPH20 and 165 for placebo) included in intention-to-treat analyses. Baseline characteristics were balanced for PEGPH20 plus AG versus placebo plus AG. There were 330 deaths, with a median OS of 11.2 months for PEGPH20 plus AG versus 11.5 months for placebo plus AG (hazard ratio [HR], 1.00; 95% CI, 0.80 to 1.27; P = .97); median PFS was 7.1 months versus 7.1 months (HR, 0.97 [95% CI, 0.75 to 1.26]); ORR was 47% versus 36% (ORR ratio, 1.29 [95% CI, 1.03 to 1.63]). Grade ≥ 3 adverse events with a ≥ 2% higher rate with PEGPH20 plus AG than with placebo plus AG included fatigue (16.0% v 9.6%), muscle spasms (6.5% v 0.6%), and hyponatremia (8.0% v 3.8%). CONCLUSION: The addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS. The safety profile of PEGPH20 plus AG was consistent with that found in previous studies. These results do not support additional development of PEGPH20 in metastatic PDA.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Anciano , Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/secundario , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Progresión de la Enfermedad , Método Doble Ciego , Fatiga/inducido químicamente , Femenino , Humanos , Ácido Hialurónico/metabolismo , Hialuronoglucosaminidasa/administración & dosificación , Hiponatremia/inducido químicamente , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Supervivencia sin Progresión , Criterios de Evaluación de Respuesta en Tumores Sólidos , Espasmo/inducido químicamente , Tasa de Supervivencia , GemcitabinaRESUMEN
Circulating cell-free mRNA (cf-mRNA) holds great promise as a non-invasive diagnostic biomarker. However, cf-mRNA composition and its potential clinical applications remain largely unexplored. Here we show, using Next Generation Sequencing-based profiling, that cf-mRNA is enriched in transcripts derived from the bone marrow compared to circulating cells. Further, longitudinal studies involving bone marrow ablation followed by hematopoietic stem cell transplantation in multiple myeloma and acute myeloid leukemia patients indicate that cf-mRNA levels reflect the transcriptional activity of bone marrow-resident hematopoietic lineages during bone marrow reconstitution. Mechanistically, stimulation of specific bone marrow cell populations in vivo using growth factor pharmacotherapy show that cf-mRNA reflects dynamic functional changes over time associated with cellular activity. Our results shed light on the biology of the circulating transcriptome and highlight the potential utility of cf-mRNA to non-invasively monitor bone marrow involved pathologies.
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Biomarcadores de Tumor/aislamiento & purificación , Médula Ósea/patología , Ácidos Nucleicos Libres de Células/aislamiento & purificación , Leucemia Mieloide Aguda/diagnóstico , Mieloma Múltiple/diagnóstico , ARN Mensajero/aislamiento & purificación , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Médula Ósea/efectos de los fármacos , Ácidos Nucleicos Libres de Células/sangre , Ácidos Nucleicos Libres de Células/genética , Estudios de Factibilidad , Perfilación de la Expresión Génica/métodos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/efectos de los fármacos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Estudios Longitudinales , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , ARN Mensajero/sangre , ARN Mensajero/genética , Análisis de Secuencia de ARN/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. METHODS: An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001). FINDINGS: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred. INTERPRETATION: Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours. FUNDING: Ignyta/F Hoffmann-La Roche.
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Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Biomarcadores de Tumor/genética , Fusión Génica , Indazoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Factor de Crecimiento Nervioso/antagonistas & inhibidores , Receptores de Factor de Crecimiento Nervioso/genética , Anciano , Antineoplásicos/efectos adversos , Benzamidas/efectos adversos , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Femenino , Humanos , Indazoles/efectos adversos , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias/genética , Neoplasias/mortalidad , Neoplasias/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Receptor trkA/antagonistas & inhibidores , Receptor trkA/genética , Receptor trkB/antagonistas & inhibidores , Receptor trkB/genética , Receptor trkC/antagonistas & inhibidores , Receptor trkC/genética , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: In this review, we highlight the pre-clinical development, recent clinical studies, and future directions of larotrectinib in patients with NTRK fusion-positive tumors. RECENT FINDINGS: The tropomyosin receptor kinase family, TrkA, TrkB, and TrkC, transmit extracellular signals via a variety of intracellular pathways to promote normal neuronal development. TrkA, B, and C are encoded by NTRK1, 2, and 3, respectively. NTRK chromosomal alterations, most commonly gene fusions, have been identified as driver mutations in a broad range of malignancies. Small molecule tyrosine kinase inhibitors of Trk, including larotrectinib, have shown broad clinical activity across multiple tumor types with NTRK fusion events. Although the prevalence of NTRK alterations is low, the exceptional activity of larotrectinib makes NTRK alterations an important predictive biomarker to screen for in any cancer.
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Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Animales , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Glicoproteínas de Membrana/antagonistas & inhibidores , Neoplasias/enzimología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Receptor trkA/antagonistas & inhibidores , Receptor trkB/antagonistas & inhibidoresRESUMEN
Checkpoint inhibitor therapy has introduced a revolution in contemporary anticancer therapy. It has led to dramatic improvements in patient outcomes and has spawned tremendous research into novel immunomodulatory agents and combination therapy that has changed the trajectory of cancer care. However, clinical benefit in patients with colorectal cancer has been generally limited to tumors with loss of mismatch repair function and those with specific germline mutations in the DNA polymerase gene. Unfortunately, tumors with these specific mutator phenotypes are in the minority. Recent pre-clinical and clinical studies have begun to reveal encouraging results suggesting that checkpoint inhibitor therapy can be expanded to an increasing number of colorectal tumors with microsatellite stability and the absence of traditional predictive biomarkers of checkpoint inhibitor response. These studies generally rely on combinations of checkpoint inhibitors with chemotherapy, molecular targeted therapy, radiation therapy, or other novel immunomodulatory agents. This article will review the most current data in microsatellite stable colorectal cancer.
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Serrated adenocarcinoma, an alternative pathway for colorectal cancer (CRC) development, accounts for 15%-30% of all CRCs and is aggressive and treatment resistant. We show that the expression of atypical protein kinase C ζ (PKCζ) and PKCλ/ι was reduced in human serrated tumors. Simultaneous inactivation of the encoding genes in the mouse intestinal epithelium resulted in spontaneous serrated tumorigenesis that progressed to advanced cancer with a strongly reactive and immunosuppressive stroma. Whereas epithelial PKCλ/ι deficiency led to immunogenic cell death and the infiltration of CD8+ T cells, which repressed tumor initiation, PKCζ loss impaired interferon and CD8+ T cell responses, which resulted in tumorigenesis. Combined treatment with a TGF-ß receptor inhibitor plus anti-PD-L1 checkpoint blockade showed synergistic curative activity. Analysis of human samples supported the relevance of these kinases in the immunosurveillance defects of human serrated CRC. These findings provide insight into avenues for the detection and treatment of this poor-prognosis subtype of CRC.
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Mucosa Intestinal/inmunología , Neoplasias Intestinales/inmunología , Isoenzimas/inmunología , Proteína Quinasa C/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Femenino , Humanos , Vigilancia Inmunológica/genética , Vigilancia Inmunológica/inmunología , Mucosa Intestinal/enzimología , Mucosa Intestinal/patología , Neoplasias Intestinales/enzimología , Neoplasias Intestinales/genética , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismoRESUMEN
CGP results from >60,000 cases were screened to identify NTRK fusion events from cases of neuroendocrine tumors. 2417 NET patients from diverse anatomic sites were identified. From this dataset, six cases harbored NTRK fusions which included intra- and inter-chromosomal translocations. A NTRK fusion frequency of approximately 0.3% was found across all subtypes of NETs. Three cases involved translocations of NTRK1 with unique fusion partners (GPATCH4, PIP5K1A, CCDC19). Co-occurring alterations occurred in five cases. NTRK alterations were identified in nearly the full spectrum of NETs, including from the small intestine, pancreas, lung, and others. With the late stage clinical development of NTRK TKIs (including entrectinib and larotrectinib), these findings may further inform targeted approaches to therapy in NET.
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Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.
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Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Hialuronoglucosaminidasa/metabolismo , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/secundario , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Enoxaparina/administración & dosificación , Femenino , Fibrinolíticos/administración & dosificación , Humanos , Ácido Hialurónico/metabolismo , Hialuronoglucosaminidasa/administración & dosificación , Masculino , Persona de Mediana Edad , Paclitaxel/efectos adversos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Supervivencia sin Progresión , Tromboembolia/inducido químicamente , Tromboembolia/prevención & control , Factores de Tiempo , GemcitabinaRESUMEN
Despite advances in genomic analysis, the molecular origin of neuroendocrine tumors (NETs) is complex and poorly explained by described oncogenes. The neurotrophic TRK family, including NTRK1, 2, and 3, encode the proteins TRKA, TRKB, TRKC, respectively, involved in normal nerve development. Because NETs develop from the diffuse neuroendocrine system, we sought to determine whether NTRK alterations occur in NETs and whether TRK-targeted therapy would be effective. A patient with metastatic well-differentiated NET, likely of the small intestine, was enrolled on the STARTRK2 trial (ClinicalTrials.gov identifier: NCT02568267) and tissue samples were analyzed using an RNA-Seq next-generation sequencing platform. An ETV6:NTRK3 fusion was identified and therapy was initiated with the investigational agent entrectinib, a potent oral tyrosine kinase inhibitor of TRKA, TRKB, and TRKC. Upon treatment with entrectinib, the patient experienced rapid clinical improvement; his tumor response was characterized by initial tumor growth and necrosis. This is the first report of an NTRK fusion in NETs. Our patient's response to entrectinib suggests that NTRK fusions can be important in the pathogenesis of NETs. Recent DNA-based genomic analyses of NETs may have missed NTRK fusions due its large gene rearrangement size and multiple fusion partners. The tumor's initial pseudoprogression may represent a unique response pattern for TRK-targeted therapies. An effort to characterize the prevalence of NTRK fusions in NETs using optimal sequencing technology is important.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/uso terapéutico , Drogas en Investigación/uso terapéutico , Indazoles/uso terapéutico , Neoplasias Intestinales/terapia , Dolor de la Región Lumbar/terapia , Tumores Neuroendocrinos/terapia , Proteínas de Fusión Oncogénica/genética , Cuidados Paliativos/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Biopsia , Quimioterapia Adyuvante/métodos , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Exones/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Intestinales/diagnóstico por imagen , Neoplasias Intestinales/genética , Neoplasias Intestinales/patología , Intestino Delgado/patología , Dolor de la Región Lumbar/etiología , Masculino , Clasificación del Tumor , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Tomografía de Emisión de Positrones/métodos , Radioterapia/métodos , Criterios de Evaluación de Respuesta en Tumores Sólidos , Análisis de Secuencia de ARN , Resultado del TratamientoRESUMEN
PURPOSE: TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. RESULTS: Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation. CONCLUSION: PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Nitroimidazoles/administración & dosificación , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Mostazas de Fosforamida/administración & dosificación , Modelos de Riesgos Proporcionales , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , GemcitabinaRESUMEN
CD22 is a member of the siglec (sialic acid-binding immunoglobulin-like lectin) family expressed on B cells that recognizes glycans of glycoproteins as ligands. Because siglecs exhibit restricted expression on one or a few leukocyte cell types, they have gained attention as attractive targets for cell-directed therapies. Several antibody-based therapies targeting CD22 (Siglec-2) are currently in clinical trials for the treatment of hairy cell leukemia and other B cell lymphomas. As an alternative to antibodies we have developed liposomal nanoparticles decorated with glycan ligands of CD22 that selectively target B cells. Because CD22 is an endocytic receptor, ligand-decorated liposomes are bound by CD22 and rapidly internalized by the cell. When loaded with a toxic cargo such as doxorubicin, they are efficacious in prolonging life in a Daudi B cell lymphoma model. These B cell targeted nanoparticles have been demonstrated to bind and kill malignant B cells from patients with hairy cell leukemia, marginal zone lymphoma and chronic lymphocytic leukemia. The results demonstrate the potential of using CD22 ligand-targeted liposomal nanoparticles as an alternative approach for the treatment of B cell malignancies.
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Antineoplásicos/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/inmunología , Nanopartículas , Polisacáridos/metabolismo , Lectina 2 Similar a Ig de Unión al Ácido Siálico/metabolismo , Humanos , Ligandos , Polisacáridos/inmunología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/químicaRESUMEN
Hairy cell leukemia (HCL) is an indolent, mature B-cell lymphoproliferative malignancy that clinically manifests as pancytopenia and fibrosis of the bone marrow, ultimately leading to recurrent infections and splenomegaly. This article reviews the extensive experience at Scripps Clinic with cladribine (2-chlorodeoxyadenosine; 2-CdA) in HCL. It is currently recommended as first-line treatment in HCL, because of its proven efficacy with associated low toxicity profile and brevity of treatment duration, with the majority of responses being complete (CRs). This was achieved after only a single 7-day infusion. We also discuss the success of cladribine in patients with relapsed and refractory HCL and potential approaches to eradicating minimal residual disease (MRD). MRD is thought to predict for future relapses. The eradication of MRD warrants continued study in order to further improve disease-free survival, which may translate into ultimately curing patients with HCL.
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Cladribina/uso terapéutico , Leucemia de Células Pilosas/tratamiento farmacológico , Humanos , Leucemia de Células Pilosas/mortalidad , Neoplasia Residual/tratamiento farmacológico , Terapia Recuperativa/métodos , Resultado del TratamientoRESUMEN
Hairy cell leukemia is a rare disease for which there are multiple treatment options. Purine nucleoside analogs (cladribine and pentostatin) are generally used for front-line treatment. Other active agents include interferon, rituximab and, although rarely, splenectomy. In the series published by Zinzani et al. in Cancer, the authors conclude that initial treatment for hairy cell leukemia should be maximized since these patients generally enjoy the highest complete response rates and the longest remission durations, and subsequent lines of therapy have lower response rates and more frequent relapses. However, evolving immunohistochemical and molecular diagnostic techniques, as well as criteria for evaluating response to therapy and clinical trials investigating chemoimmunotherapy, may result in clinicians re-evaluating how patients are treated in the front-line and when treatment should be initiated for relapsed patients.