RESUMEN
Purpose: To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection.Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures.Results: Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype (P = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients.Conclusions: Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes. Clin Cancer Res; 24(6); 1344-54. ©2017 AACR.
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Genómica , Neoplasias Pancreáticas/genética , Medicina de Precisión , Adulto , Anciano , Biomarcadores de Tumor , Ensayos Clínicos como Asunto , Daño del ADN , Manejo de la Enfermedad , Progresión de la Enfermedad , Femenino , Factor de Transcripción GATA6/genética , Genómica/métodos , Humanos , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Medicina de Precisión/métodos , Transcriptoma , Secuenciación del ExomaRESUMEN
AIM: This phase I/II study of saracatinib in combination with gemcitabine in patients with advanced pancreatic cancer was conducted by the NCIC Clinical Trials Group. The aims were to define the recommended phase II dose (RP2D) of saracatinib when combined with gemcitabine, and assess the efficacy of this combination in advanced pancreatic cancer. PATIENTS AND METHODS: Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and no prior chemotherapy. In phase I saracatinib was escalated in combination with gemcitabine (1000 mg/m(2)) to determine the recommended phase II dose (RP2D). The study was then expanded to a single arm phase II trial using a Simon 2-stage design. The primary endpoint was objective tumor response (OR) plus stable disease ≥ 4 months (SD4) rate; if ≥ 8 patients had OR+SD4, the study would proceed to stage 2. RESULTS: Thirteen patients were enrolled into the phase I portion of this study. Saracatinib 175 mg PO daily was chosen as the RP2D in combination with gemcitabine. Twenty-one additional patients were then enrolled at the RP2D (phase II). Of the 22 response evaluable patients treated at the RP2D, 9 patients (40.9%) had progressive disease, 6 patients (27.3%) had stable disease for less than 4 months, 5 patients (22.7%) had SD4, and 2 patients (9.1%) had a partial response to treatment. Objective criteria for continuing to stage 2 were thus not met and the trial was closed following the accrual of 34 patients. CONCLUSION: Saracatinib 175 mg daily in combination with gemcitabine is well tolerated but the combination did not improve efficacy over what would be expected from gemcitabine alone.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Familia-src Quinasas/antagonistas & inhibidores , Administración Oral , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzodioxoles/administración & dosificación , Canadá , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/administración & dosificación , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Familia-src Quinasas/metabolismo , GemcitabinaRESUMEN
PURPOSE: To evaluate the feasibility and safety of concurrent pemetrexed/cisplatin/thoracic radiotherapy followed by consolidation pemetrexed/cisplatin for unresectable Stage IIIA/B non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Eligible patients with <5% weight loss and good performance status received two cycles of pemetrexed (300, 400, or 500 mg/m(2) on Days 1 and 22 for Dose Levels 1, 2, and 3/4, respectively) and cisplatin (25 mg/m(2) Days 1-3 for Dose Levels 1-3; 20 mg/m(2) Days 1-5 for Dose Level 4) concurrent with thoracic radiation (61-66 Gy in 31-35 fractions). Consolidation consisted of two cycles of pemetrexed/cisplatin (500 mg/m(2), 75 mg/m(2)) 21 days apart, after concurrent therapy. RESULTS: Between January 2006 and October 2007, 16 patients entered the study. Median follow-up was 17.2 months. No dose-limiting toxicities were observed. Median radiation dose was 64 Gy (range, 45-66 Gy). Rates of significant Grade 3/4 hematologic toxicity were 38% and 7%, respectively. One patient experienced Grade 3 acute esophagitis, and 2 experienced late (Grade 3) esophageal stricture, successfully managed with dilation. One patient experienced Grade 3 pneumonitis. The overall response rate was 88%. One-year overall survival was 81%. CONCLUSIONS: Full systemic dose pemetrexed seems to be safe with full-dose cisplatin and thoracic radiation in Stage IIIA/B NSCLC. Pemetrexed is the first third-generation cytotoxic agent tolerable at full dose in this setting. A Phase II study evaluating Dose Level 4 is ongoing.