RESUMO
AbGn-107 is an antibody-drug conjugate directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in a variety of gastrointestinal (GI) malignancies. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a GI cancer-specific Phase I trial. Standard 3 + 3 dose escalation was used evaluating intravenous doses ranging from 0.1 mg/kg every 4 weeks to 1.0 mg/kg every 2 weeks. Key eligibility included chemo-refractory locally advanced, recurrent, or metastatic gastric, colorectal, pancreatic, or biliary cancer, with ECOG PS 0-1; positive AG-7 expression was not required during dose escalation phase. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments every 8 weeks. Primary objectives included safety and determination of maximum tolerated dose; secondary objectives included efficacy defined by objective response rate. Thirty-nine patients were enrolled across seven dose levels during dose escalation phase. Based on safety profile and pharmacokinetic data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase, in which an additional seven patients were enrolled. Median number of lines of prior therapy was 3 (range 1-7). AbGn-107 was generally well-tolerated, with infections, cytopenias, hyponatremia, fatigue, abdominal pain, and diarrhea representing the most common grade 3 or higher treatment-emergent adverse events. One subject achieved a partial response, while 18 (46.2%) achieved a best response of stable disease. Disease control lasting > 6 months was observed in 6 subjects (13.0%), including 4 of 15 (26.7%) treated at the highest dose level. AbGn-107 showed a reasonable safety profile and modest clinical activity in this highly pretreated patient population. Further evaluation is required to assess the clinical validity of AG-7 as a suitable antigen for therapeutic targeting. Clinical Trial information: NCT02908451.
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Neoplasias Gastrointestinais , Imunoconjugados , Humanos , Imunoconjugados/efeitos adversos , Neoplasias Gastrointestinais/tratamento farmacológico , Dose Máxima TolerávelRESUMO
Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas is a rare and potentially aggressive variant of pancreatic ductal adenocarcinoma. Data on this disease are sparse, and despite genetic similarities to pancreatic ductal adenocarcinoma, UCOGC clinical outcomes can be markedly different. We report on a female patient aged 62 years who presented with UCOGC with pulmonary metastases initially treated with 2 lines of cytotoxic chemotherapy. After rapid disease progression with both cytotoxic treatments, the patient's tissue was sent for next-generation sequencing, which revealed a high tumor mutation burden (32 mutations per megabase), as well as somatic mutations in BRAF, NF1, PIK3CA, CDKN2A, TERT, and TP53. Pancreatic cancers have previously demonstrated suboptimal responses to immunotherapeutic approaches. However, given the high tumor mutation burden and distinctiveness of the tumor class, the patient began third-line pembrolizumab monotherapy after palliative radiation to the rapidly progressing and painful abdominal mass from her primary tumor. She had a marked response in her primary UCOGC tumor and metastatic sites, and she remains on pembrolizumab monotherapy with ongoing response after 32 months of therapy. Recent evidence showing significant PD-L1 enrichment on neoplastic cells of undifferentiated carcinomas (including UCOGC) may indicate a role for immunotherapeutic approaches in these patients. Rare cancers such as UCOGC and other undifferentiated carcinomas may benefit from next-generation sequencing to inform treatment decisions when standards of care are absent, as in this report.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Feminino , Células Gigantes , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Osteoclastos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologiaRESUMO
BACKGROUND: In the setting of multidisciplinary standardized care of locally advanced rectal cancer, preoperative chemoradiotherapy and total mesorectal excision have become the mainstay treatment. OBJECTIVE: This study aimed to evaluate whether the lack of preoperative chemoradiotherapy or poor response to it is associated with higher radial margin disease involvement in patients with locally advanced rectal cancer. DESIGN: This is a retrospective cohort study using a publicly available database. SETTING: Data were collected from the proctectomy-targeted National Surgical Quality Improvement Project file from 2016 to 2017. PATIENTS: A total of 1161 patients were analyzed. They were categorized into 3 groups: patients who did not receive any preoperative chemoradiotherapy (28.6%), patients who received and responded to preoperative chemoradiotherapy (41.2%), and patients who received but did not respond to preoperative chemoradiotherapy (30.2%). MAIN OUTCOME MEASURES: Response to treatment was determined by using the American Joint Committee on Cancer pretreatment and final pathological staging. Circumferential radial margin was extracted from the targeted proctectomy file. RESULTS: Disease-involved positive circumferential radial margin was found in 86 (7.4%) cases. Positive radial margin was noted in 11 of 479 patients (2.3%) who underwent preoperative chemoradiotherapy and responded to treatment, 30 of 350 patients (8.6%) who did not respond or had a poor response to preoperative chemoradiotherapy, and 45 of 332 patients (13.6%) who did not receive preoperative chemoradiotherapy (p < 0.001). Regression analysis demonstrated that patients who do not receive preoperative chemoradiotherapy or have poor response to it have 6.6 and 4 times higher chances of having a positive radial margin. LIMITATIONS: There is a risk of selection bias, unidentified confounders, and missing data despite the use of a nationwide cohort. CONCLUSIONS: Omission of indicated preoperative chemoradiotherapy or poor response to it is associated with increased risk of radial margin positivity. More efforts are needed for standardized rectal cancer care with the appropriate use of preoperative chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/B467. LA OMISIN O LA ESCASA RESPUESTA A QUIMIORADIOTERAPIA PREOPERATORIA, AFECTA LAS TASAS DE POSITIVIDAD DEL MARGEN RADIAL, EN EL CNCER RECTAL LOCALMENTE AVANZADO: ANTECEDENTES:En el contexto de la atención multidisciplinaria estandarizada del cáncer rectal localmente avanzado, la quimioradioterapia preoperatoria y la escisión mesorrectal total, se han convertido en el tratamiento principal.OBJETIVO:Evaluar si la omisión de quimioradioterapia preoperatoria o la escasa respuesta, se asocia con mayor enfermedad del margen radial, en pacientes con cáncer rectal localmente avanzado.DISEÑO:Estudio de cohorte retrospectivo utilizando una base de datos disponible públicamente.AJUSTE:Se recopilaron datos del archivo del Proyecto Nacional de Mejora de la Calidad Quirúrgica dirigido a la proctectomía de 2016-2017.PACIENTES:Se analizaron un total de 1161 pacientes. Clasificados en tres grupos: pacientes que no recibieron quimioradioterapia preoperatoria (28,6%), pacientes que recibieron y respondieron a quimioradioterapia preoperatoria (41,2%) y pacientes que recibieron pero no respondieron a la quimioradioterapia preoperatoria (30,2%).PRINCIPALES MEDIDAS DE RESULTADO:La respuesta al tratamiento se determinó utilizando el pre tratamiento y la estatificación patológica final, del American Joint Committee on Cancer. El margen radial circunferencial se extrajo del archivo de proctectomía dirigida.RESULTADOS:Se encontró enfermedad que abarcaba el margen radial circunferencial +, en el 86 (7,4%) casos. Se observó el margen radial +, en 11 de 479 pacientes (2,3%) que se sometieron a quimioradioterapia preoperatoria y respondieron al tratamiento, 30 de 350 pacientes (8,6%) que no respondieron o tuvieron una mala respuesta con quimioradioterapia preoperatoria y en 45 de 332 pacientes (13,6%) que no recibieron quimioradioterapia preoperatoria (p <0,001). El análisis de regresión demostró que los pacientes que no reciben quimioradioterapia preoperatoria o que tienen escasa respuesta, presentan respectivamente, 6,6 y 4 veces más probabilidades de tener un margen radial +.LIMITACIONES:Existe el riesgo de sesgo de selección, factores de confusión no identificados y datos faltantes a pesar del uso de una cohorte nacional.CONCLUSIONES:La omisión de la quimioradioterapia preoperatoria indicada o la escasa respuesta, se asocian a un mayor riesgo de positividad del margen radial. Se necesitan mayores esfuerzos en la atención estandarizada del cáncer rectal, con el uso adecuado de quimioradioterapia preoperatoria. Consulte Video Resumen en http://links.lww.com/DCR/B467.
Assuntos
Terapia Neoadjuvante/efeitos adversos , Cuidados Pré-Operatórios/métodos , Protectomia/métodos , Neoplasias Retais/cirurgia , Idoso , Estudos de Coortes , Gerenciamento de Dados , Feminino , Humanos , Comunicação Interdisciplinar , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Terapia Neoadjuvante/estatística & dados numéricos , Estadiamento de Neoplasias/métodos , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/epidemiologia , Protectomia/estatística & dados numéricos , Neoplasias Retais/patologia , Análise de Regressão , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
In 2016, the American Society of Clinical Oncology published a guideline recommending that all patients with advanced cancer be referred to palliative care providers. This recommendation was based on a series of trials showing that palliative care, when added to standard oncology treatment, improves outcomes, including quality of life. Here, 2 oncologists, 1 of whom is also a palliative care specialist, debate the guideline and discuss how best to care for a 71-year-old woman with metastatic neuroendocrine carcinoma who has a short life expectancy but feels well and has no symptoms related to her cancer or chemotherapy.
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Carcinoma Neuroendócrino/terapia , Neoplasias Hepáticas/terapia , Cuidados Paliativos , Encaminhamento e Consulta , Planejamento Antecipado de Cuidados , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/secundário , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Oncologistas , Equipe de Assistência ao Paciente , Papel do Médico , Guias de Prática Clínica como Assunto , Visitas de PreceptoriaRESUMO
BACKGROUND/OBJECTIVES: To determine the prevalence of incidental pulmonary embolism (PE) detected during initial staging CT among patients with newly diagnosed pancreatic ductal adenocarcinoma (PDAC) and assess their association with underlying tumor burden. MATERIALS AND METHODS: This retrospective cohort study evaluated staging chest CT scans (2013-2017) to identify PE among patients with treatment naïve, biopsy-proven PDAC. Data included age, sex, T stage, AJCC stage, presence/absence of metastases and their location at diagnosis. The association of PE with tumor (T1-T4) and AJCC stage were assessed using Pearson Chi-square and Fischer's exact test. A threshold p-value of <0.05 indicated statistical significance. RESULTS: A total of 174 patients (90 female, mean age, 68 years; range: 34-93) were identified, of which 10 patients harbored incidental PE (prevalence, 5.7%). In the PE group, two patients presented with distant metastasis (liver, 20%), while eight patients had T4 tumors (80%). No statistical association was detected between PE and age, sex, and the presence/absence or location of distant metastasis (pâ¯=â¯0.065, pâ¯=â¯0.59, pâ¯=â¯0.687 and pâ¯=â¯0.933, respectively). Patients with T4 tumors and higher AJCC stages (stage III/IV) were significantly more likely to present with PE than those with lower T stage (pâ¯=â¯0.045) and AJCC stage (stage I/II; pâ¯=â¯0.017). CONCLUSION: The prevalence of incidental PE among PDAC patients undergoing initial CT staging is 5.7%. Patients with T4 and AJCC stages III/IV are at higher risk of PE. Caution should be exercised during radiographic interpretation of initial staging chest CTs, as incidental PE may be lurking and require treatment.
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Carcinoma Ductal Pancreático/complicações , Carcinoma Ductal Pancreático/patologia , Embolia/diagnóstico , Embolia/patologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/terapia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/terapia , Estudos RetrospectivosRESUMO
The vascular endothelium and shear stress are critical determinants of physiological hemostasis and platelet function in vivo, yet current diagnostic and monitoring devices do not fully incorporate endothelial function under flow in their assessment and, therefore, they can be unreliable and inaccurate. It is challenging to include the endothelium in assays for clinical laboratories or point-of-care settings because living cell cultures are not sufficiently robust. Here, we describe a microfluidic device that is lined by a human endothelium that is chemically fixed, but still retains its ability to modulate hemostasis under continuous flow in vitro even after few days of storage. This device lined with a fixed endothelium supports formation of platelet-rich thrombi in the presence of physiological shear, similar to a living arterial vessel. We demonstrate the potential clinical value of this device by showing that thrombus formation and platelet function can be measured within minutes using a small volume (0.5 mL) of whole blood taken from subjects receiving antiplatelet medications. The inclusion of a fixed endothelial microvessel will lead to biomimetic analytical devices that can potentially be used for diagnostics and point-of-care applications.
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Endotélio Vascular/efeitos dos fármacos , Dispositivos Lab-On-A-Chip , Trombose/diagnóstico , Plaquetas/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Fibrina/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Inibidores da Agregação Plaquetária/farmacologia , Sistemas Automatizados de Assistência Junto ao Leito , Estresse Mecânico , Trombose/sangue , Trombose/tratamento farmacológicoAssuntos
Neoplasias , Visitas de Preceptoria , Humanos , Israel , Cuidados Paliativos , Encaminhamento e ConsultaRESUMO
The CCR/L5 axis is known for its role in immune regulation in a variety of settings and has been shown to have dichotomous functions in cancer, influencing both tumor progression and immune responses. Battaglin et al investigated its role using genomic and transcriptomic data from several datasets of patients with advanced colorectal cancer (CRC), including patients treated on CALGB/SWOG 80405, a trial of chemotherapy plus cetuximab versus bevacizumab, as well as a larger population of patients whose CRCs underwent commercially available Caris NGS and CODEai assays. These authors showed that CCR/L5 expression was both prognostic and predictive. They reported that low expression of the CCR/L5 axis was correlated with improved survival broadly, with particular benefit in patients treated with chemotherapy plus cetuximab. They demonstrated that high expression of CCR/L5 was associated with infiltration by negatively prognostic Tregs, M1 and M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts. They also showed that increased expression was correlated a wide variety of immune suppressive proteins, including PD-1, PD-L1, PD-L2, CTLA4, CD80, CD86, TIM3, IDO1, LAG3, and IFN-γ. This suggests mechanisms by which CRC resists anti-cancer immune responses. This study enhances our understanding of the role of the CCR/L5 axis in advanced CRC.
Assuntos
Quimiocina CCL5 , Neoplasias Colorretais , Receptores CCR5 , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Receptores CCR5/metabolismo , Receptores CCR5/genética , Quimiocina CCL5/metabolismo , Quimiocina CCL5/genética , Metástase NeoplásicaRESUMO
Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 .
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Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Here we report clinical and translational results from a phase Ib trial testing whether IL-1ß blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal antitumor T-cell responses to PD-1 blockade. Patients with treatment-naïve advanced pancreatic ductal adenocarcinoma (n=10) were treated with canakinumab, a high-affinity monoclonal human anti-interleukin-1ß (IL-1ß), the PD-1 blocking antibody spartalizumab, and gemcitabine/n(ab)paclitaxel. Analysis of paired peripheral blood from patients in the trial versus patients receiving multiagent chemotherapy showed a modest increase in HLA-DR+CD38+ activated CD8+ T cells and a decrease in circulating monocytic myeloid-derived suppressor cells (MDSCs) by flow cytometry for patients in the trial, but not in controls. Similarly, we used patient serum to differentiate monocytic MDSCs in vitro and showed that functional inhibition of T-cell proliferation was reduced when using on-treatment serum samples from patients in the trial but not when using serum from patients treated with chemotherapy alone. Within the tumor we observed few changes in suppressive myeloid-cell populations or activated T cells as assessed by single-cell transcriptional profiling or multiplex immunofluorescence, although increases in CD8+ T cells suggest that improvements in the tumor immune microenvironment might be revealed by a larger study. Overall, the data indicate that exposure to PD-1 and IL-1ß blockade induced a modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs; however, these changes did not lead to similarly uniform alterations in the tumor microenvironment.
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PURPOSE: ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known. EXPERIMENTAL DESIGN: Dana-Farber and Foundation Medicine Inc. Colorectal cancer cohorts with genomic profiling were used to identify ERBB2-amplified cases [Dana-Farber, n = 47/2,729 (1.7%); FMI, n = 1857/49,839 (3.7%)]. Outcomes of patients receiving HER2-directed therapies are reported (Dana-Farber, n = 9; Flatiron Health-Foundation Medicine clinicogenomic database, FH-FMI CGDB, n = 38). Multisite HER2 IHC and genomic profiling were performed to understand HER2 intratumoral and interlesional heterogeneity. The impact of concurrent RAS comutations on the effectiveness of HER2-directed therapies were studied in isogenic colorectal cancer cell lines and xenografts. RESULTS: ERBB2 amplifications are enriched in left-sided colorectal cancer. Twenty percent of ERBB2-amplified colorectal cancers have co-occurring oncogenic RAS/RAF alterations. While RAS/RAF WT colorectal cancers typically have clonal ERBB2 amplification, colorectal cancers with co-occurring RAS/RAF alterations have lower level ERRB2 amplification, higher intratumoral heterogeneity, and interlesional ERBB2 discordance. These distinct genomic patterns lead to differential responsiveness and patterns of resistance to HER2-directed therapy. ERBB2-amplified colorectal cancer with RAS/RAF alterations are resistant to trastuzumab-based combinations, such as trastuzumab/tucatinib, but retain sensitivity to trastuzumab deruxtecan in in vitro and murine models. Trastuzumab deruxtecan shows clinical efficacy in cases with high-level ERBB2-amplified RAS/RAF coaltered colorectal cancer. CONCLUSIONS: Co-occurring RAS/RAF alterations define a unique subtype of ERBB2-amplified colorectal cancer that has increased intratumoral heterogeneity, interlesional discordance, and resistance to trastuzumab-based combinations. Further examination of trastuzumab deruxtecan in this previously understudied cohort of ERBB2-amplified colorectal cancer is warranted.
Assuntos
Neoplasias Colorretais , Variações do Número de Cópias de DNA , Humanos , Animais , Camundongos , Amplificação de Genes , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Receptor ErbB-2/metabolismo , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Resultado do Tratamento , MutaçãoRESUMO
Importance: Treatment options are limited for patients with advanced pancreatic ductal adenocarcinoma (PDAC) beyond first-line 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), with such individuals commonly being treated with gemcitabine and nab-paclitaxel. Objective: To determine whether NPC-1C, an antibody directed against MUC5AC, might increase the efficacy of second-line gemcitabine and nab-paclitaxel in patients with advanced PDAC. Design, Setting, and Participants: This multicenter, randomized phase II clinical trial enrolled patients with advanced PDAC between April 2014 and March 2017 whose disease had progressed on first-line FOLFIRINOX. Eligible patients had tumors with at least 20 MUC5AC staining by centralized immunohistochemistry review. Statistical analysis was performed from April to May 2022. Interventions: Patients were randomly assigned to receive gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) administered intravenously on days 1, 8, and 15 of every 4-week cycle, with or without intravenous NPC-1C 1.5 mg/kg every 2 weeks. Main Outcomes and Measures: The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. Pretreatment clinical variables were explored with Cox proportional hazards analysis. Results: A total of 78 patients (median [range] age, 62 [36-78] years; 32 [41%] women; 9 [12%] Black; 66 [85%] White) received second-line treatment with gemcitabine plus nab-paclitaxel (n = 40) or gemcitabine plus nab-paclitaxel and NPC-1C (n = 38). Median OS was 6.6 months (95% CI, 4.7-8.4 months) with gemcitabine plus nab-paclitaxel vs 5.0 months (95% CI, 3.3-6.5 months; P = .22) with gemcitabine plus nab-paclitaxel and NPC-1C. Median PFS was 2.7 months (95% CI, 1.9-4.1 months) with gemcitabine plus nab-paclitaxel vs 3.4 months (95% CI, 1.9-5.3 months; P = .80) with gemcitabine plus nab-paclitaxel and NPC-1C. The ORR was 3.1% (95% CI, 0.4%-19.7%) in the gemcitabine plus nab-paclitaxel and NPC-1C group and 2.9% (95% CI, 0.4%-18.7%) in the gemcitabine plus nab-paclitaxel group. No differences in toxicity were observed between groups, except that grade 3 or greater anemia occurred more frequently in patients treated with gemcitabine plus nab-paclitaxel and NPC-1C than gemcitabine plus nab-paclitaxel (39% [15 of 38] vs 10% [4 of 40]; P = .003). The frequency of chemotherapy dose reductions was similar in both groups (65% vs 74%; P = .47). Lower performance status, hypoalbuminemia, PDAC diagnosis less than or equal to 18 months before trial enrollment, lymphocyte-to-monocyte ratio less than 2.8, and CA19-9 greater than 2000 IU/mL were independently associated with poorer survival. Conclusions and Relevance: In this randomized clinical trial of advanced PDAC, NPC-1C did not enhance the efficacy of gemcitabine/nab-paclitaxel. These data provide a benchmark for future trials investigating second-line treatment of PDAC. Trial Registration: ClinicalTrials.gov Identifier: NCT01834235.
Assuntos
Adenocarcinoma , Anticorpos Monoclonais , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Gencitabina/uso terapêutico , Mucina-5AC/uso terapêutico , Paclitaxel/uso terapêutico , Adulto , Idoso , Neoplasias PancreáticasRESUMO
PURPOSE: GI cancers commonly spread to the peritoneal cavity, particularly from primary adenocarcinomas of the stomach and appendix. Peritoneal metastases are difficult to visualize on cross-sectional imaging and cause substantial morbidity and mortality. The purpose of this study was to determine whether serial highly sensitive tumor-informed circulating tumor DNA (ctDNA) measurements could longitudinally track changes in disease burden and inform clinical care. METHODS: This was a retrospective case series of patients with gastric or appendiceal adenocarcinoma and isolated peritoneal disease that was radiographically occult. Patients underwent quantitative tumor-informed ctDNA testing (Signatera) as part of routine clinical care. No interventions were prespecified based on ctDNA results. RESULTS: Of 13 patients studied, the median age was 65 (range, 45-75) years, with 7 (54%) women, 5 (38%) patients with gastric, and 8 (62%) patients with appendiceal adenocarcinoma. Eight (62%) patients had detectable ctDNA at baseline measurement, with median value 0.13 MTM/mL (range, 0.06-11.68), and assay was technically unsuccessful in two cases with appendiceal cancer because of limited tumor tissue. Five (100%) patients with gastric cancer and 3 (50%) patients with appendiceal cancer had detectable ctDNA at baseline. Although baseline levels of ctDNA were low, longitudinal assessment tracked with changes in disease burden among patients undergoing chemotherapy for metastatic disease. In two patients undergoing surveillance after definitive surgical management of gastric adenocarcinoma, detection of ctDNA prompted diagnosis of isolated peritoneal disease. CONCLUSION: Quantitative tumor-informed serial ctDNA testing aids clinical management of patients with isolated peritoneal disease. Low levels of baseline ctDNA suggest a role for highly sensitive ctDNA approaches over panel-based testing. Further exploration of this approach should be considered in patients with isolated peritoneal malignant disease.
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Adenocarcinoma , Neoplasias do Apêndice , DNA Tumoral Circulante , Neoplasias Peritoneais , Neoplasias Gástricas , Humanos , Feminino , Idoso , Masculino , DNA Tumoral Circulante/genética , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/genética , Estudos Retrospectivos , Biomarcadores Tumorais/genética , DNA de Neoplasias/genéticaRESUMO
PURPOSE: Combining gemcitabine with CHK1 inhibition has shown promise in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Here, we report the findings from a phase I expansion cohort study (NCT02632448) investigating low-dose gemcitabine combined with the CHK1 inhibitor LY2880070 in patients with previously treated advanced PDAC. PATIENTS AND METHODS: Patients with metastatic PDAC were treated with gemcitabine intravenously at 100 mg/m2 on days 1, 8, and 15, and LY2880070 50 mg orally twice daily on days 2-6, 9-13, and 16-20 of each 21-day cycle. Pretreatment tumor biopsies were obtained from each patient for correlative studies and generation of organoid cultures for drug sensitivity testing and biomarker analyses. RESULTS: Eleven patients with PDAC were enrolled in the expansion cohort between August 27, 2020 and July 30, 2021. Four patients (36%) experienced drug-related grade 3 adverse events. No objective radiologic responses were observed, and all patients discontinued the trial by 3.2 months. In contrast to the lack of efficacy observed in patients, organoid cultures derived from biopsies procured from two patients demonstrated strong sensitivity to the gemcitabine/LY2880070 combination and showed treatment-induced upregulation of replication stress and DNA damage biomarkers, including pKAP1, pRPA32, and γH2AX, as well as induction of replication fork instability. CONCLUSIONS: No evidence of clinical activity was observed for combined low-dose gemcitabine and LY2880070 in this treatment-refractory PDAC cohort. However, the gemcitabine/LY2880070 combination showed in vitro efficacy, suggesting that drug sensitivity for this combination in organoid cultures may not predict clinical benefit in patients.
Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Quinase 1 do Ponto de Checagem , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Estudos de Coortes , Desoxicitidina , Gencitabina , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
PURPOSE: Approximately 8% to 10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for clinical trials of molecularly targeted agents. EXPERIMENTAL DESIGN: We analyzed a single-institution cohort of 795 exocrine pancreatic cancer cases (including 785 PDAC cases) with a targeted multigene sequencing panel and identified 73 patients (9.2%) with KRAS wild-type (WT) pancreatic cancer. RESULTS: Overall, 43.8% (32/73) of KRAS WT cases had evidence of an alternative driver of the MAPK pathway, including BRAF mutations and in-frame deletions and receptor tyrosine kinase fusions. Conversely, 56.2% of cases did not harbor a clear MAPK driver alteration, but 29.3% of these MAPK-negative KRAS WT cases (12/41) demonstrated activating alterations in other oncogenic drivers, such as GNAS, MYC, PIK3CA, and CTNNB1. We demonstrate potent efficacy of pan-RAF and MEK inhibition in patient-derived organoid models carrying BRAF in-frame deletions. Moreover, we demonstrate durable clinical benefit of targeted therapy in a patient harboring a KRAS WT tumor with a ROS1 fusion. Clinically, patients with KRAS WT tumors were significantly younger in age of onset (median age: 62.6 vs. 65.7 years; P = 0.037). SMAD4 mutations were associated with a particularly poor prognosis in KRAS WT cases. CONCLUSIONS: This study defines the genomic underpinnings of KRAS WT pancreatic cancer and highlights potential therapeutic avenues for future investigation in molecularly directed clinical trials. See related commentary by Kato et al., p. 4527.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Mutação , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genéticaRESUMO
Rectal cancer is an aggressive subtype of colon cancer with inferior outcomes in terms of disease-free and overall survival. Localized rectal cancer should be managed surgically. For stage II and III rectal cancer, neoadjuvant radiation, either as long-course chemoradiotherapy with a sensitizing fluoropyrimidine or short-course radiation, should be offered in all cases. Adjuvant or neoadjuvant fluoropyrimidine and oxaliplatin chemotherapy also should be given. In general, rectal cancer should be treated with a radiation-first approach, but the exact sequencing of therapy does not seem to significantly impact overall survival but rather toxicity, pathologic responses, compliance, and cost.
Assuntos
Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia , Quimioterapia Adjuvante , Fluoruracila/uso terapêutico , Humanos , Terapia Neoadjuvante , Estadiamento de Neoplasias , Oxaliplatina/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/terapiaRESUMO
Although studies have demonstrated the 12-gene Oncotype DX Colon Recurrence Score's (RS) validity in predicting recurrence and influence on physician-patient decision-making, its discriminatory power and inability to predict response to treatment make its clinical impact uncertain. We sought to evaluate the influence of RS in the decision to offer adjuvant chemotherapy after resection of stage IIa colon cancer. A review of patients with stage IIa colon cancer who obtained the RS at a tertiary academic medical center was conducted. The main study outcome was decision to start adjuvant chemotherapy. The association between RS and the decision to obtain adjuvant chemotherapy was evaluated utilizing the Wilcoxon rank-sum test and area under the receiver operating characteristic curve. 52 of 105 patients with stage IIa colon cancer underwent RS testing. Overall, seven of 52 patients (13%) received adjuvant chemotherapy. 34 (65%) patients obtained the RS test despite having multiple other recurrence risk factors. There were no significant associations between any patient/tumor characteristic and RS score (all p > 0.08) or starting adjuvant chemotherapy (all p > 0.15). On multivariable analysis, there was no significant effect of RS on the odds of undergoing chemotherapy (OR 1.07, 95% CI 0.98-1.19; p = 0.14). There was no clear association between RS and starting adjuvant chemotherapy (AUC 0.64, 95% CI 0.36-0.91; p = 0.25). RS was not associated with the decision to start adjuvant chemotherapy. Given its lack of association with clinical decision-making and inability to predict clinical outcome, our data suggest the RS should not be obtained in patients with stage IIa colon cancer.
Assuntos
Neoplasias do Colo/diagnóstico , Neoplasias do Colo/patologia , Recidiva Local de Neoplasia/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/cirurgia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/tratamento farmacológico , Estadiamento de Neoplasias , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de RiscoRESUMO
Hospitalized patients with cancer are at an increased risk of developing venous thromboembolism (VTE). The recommendation for routine pharmacologic thromboprophylaxis in hospitalized patients with cancer to prevent VTE is based on extrapolation of results from noncancer cohorts. There are limited data to support the efficacy and safety of fixed-dose low-molecular-weight heparin (LMWH) regimens in high-risk hospitalized patients with cancer. We conducted a randomized, double-blinded, phase 2 trial in hospitalized patients with active cancer at high risk of developing VTE based on Padua risk score. Patients were randomly assigned to fixed-dose enoxaparin (40 mg daily) vs weight-adjusted enoxaparin (1 mg/kg daily) during hospitalization. The primary objectives were to evaluate the safety of dose-adjusted enoxaparin and evaluate the incidence of VTE with fixed-dose enoxaparin. Blinded clinical assessments were performed at day 14, and patients randomly assigned to fixed-dose enoxaparin subsequently underwent a bilateral lower extremity ultrasound. A total of 50 patients were enrolled and randomized. The median weight of patients enrolled in weight-adjusted enoxaparin arm was 76 kg (range, 60.9-124.5 kg). There were no major hemorrhages or symptomatic VTE in either arm. At time of completion of the blinded clinical assessment, there was only 1 incidentally identified pulmonary embolus that occurred in the weight-adjusted arm. In the group randomly assigned to fixed-dose enoxaparin who subsequently underwent surveillance ultrasound, the cumulative incidence of DVT was 22% (90% binomial confidence interval, 0%-51.3%). This phase 2 trial confirms a high incidence of asymptomatic VTE among high-risk hospitalized patients with cancer and that weight-adjusted LMWH thromboprophylaxis is feasible and well-tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02706249.
Assuntos
Neoplasias , Tromboembolia Venosa , Anticoagulantes/efeitos adversos , Enoxaparina/efeitos adversos , Heparina de Baixo Peso Molecular/efeitos adversos , Humanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controleRESUMO
BACKGROUND: Protein disulfide isomerase (PDI) is a thiol isomerase secreted by vascular cells that is required for thrombus formation. Quercetin flavonoids inhibit PDI activity and block platelet accumulation and fibrin generation at the site of a vascular injury in mouse models, but the clinical effect of targeting extracellular PDI in humans has not been studied. METHODS: We conducted a multicenter phase II trial of sequential dosing cohorts to evaluate the efficacy of targeting PDI with isoquercetin to reduce hypercoagulability in cancer patients at high risk for thrombosis. Patients received isoquercetin at 500 mg (cohort A, n = 28) or 1000 mg (cohort B, n = 29) daily for 56 days, with laboratory assays performed at baseline and the end of the study, along with bilateral lower extremity compression ultrasound. The primary efficacy endpoint was a reduction in D-dimer, and the primary clinical endpoint included pulmonary embolism or proximal deep vein thrombosis. RESULTS: The administration of 1000 mg isoquercetin decreased D-dimer plasma concentrations by a median of -21.9% (P = 0.0002). There were no primary VTE events or major hemorrhages observed in either cohort. Isoquercetin increased PDI inhibitory activity in plasma (37.0% in cohort A, n = 25, P < 0.001; 73.3% in cohort B, n = 22, P < 0.001, respectively). Corroborating the antithrombotic efficacy, we also observed a significant decrease in platelet-dependent thrombin generation (cohort A median decrease -31.1%, P = 0.007; cohort B median decrease -57.2%, P = 0.004) and circulating soluble P selectin at the 1000 mg isoquercetin dose (median decrease -57.9%, P < 0.0001). CONCLUSIONS: Isoquercetin targets extracellular PDI and improves markers of coagulation in advanced cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT02195232. FUNDING: Quercegen Pharmaceuticals; National Heart, Lung, and Blood Institute (NHLBI; U54HL112302, R35HL135775, and T32HL007917); and NHLBI Consortium Linking Oncology and Thrombosis (U01HL143365).