BRAFV600E/RAS Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors

Mutació BRAF; Síndrome de Lynch; Inhibidors del punt de control immunològicMutación BRAF; Síndrome de Lynch; Inhibidores de punto de control inmunológicoBRAF mutation; Lynch syndrome; Immune checkpoint inhibitorsBackground We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS). Patients and Methods Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAFV600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P < .2) if limited number of events. Results Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 in the total population, 111 (24.0%) were treated in first-line; 129 (28.8%) were BRAFV600E-mutated and 153 (32.8%) RAS-mutated. Median follow-up was 20.9 months. In adjusted analysis of the whole population (PFS/OS events = 186/133), no associations with PFS and OS were observed for BRAFV600E-mutated (PFS HR= 1.20, P = .372; OS HR = 1.06, P = .811) and RAS-mutated patients (PFS HR = 0.93, P = .712, OS HR = 0.75, P = .202). In adjusted analysis in the Lynch/sporadic status-assigned population (n = 242; PFS/OS events = 80/54), LS-liked patients had an improved PFS compared to sporadic cases (HR = 0.49, P = .036). The adjusted HR for OS was 0.56 with no significance (P = .143). No adjustment on BRAFV600E mutation was done due to collinearity. Conclusion In this cohort, RAS/BRAFV600E mutations were not associated with survival while LS conferred an improved PFS.This research did not receive any specific grant from funding of industry; partially funded by IOVIRCCS 5x1000 Grant, Missoni Project, code BIGID219ZAGO, and by Association de Recherche en Oncologie Saint-Antoine (AROSAT)

MMB & DFT 2014 : Proceedings of the International Workshops ; Modeling, Analysis and Management of Social Networks and their Applications (SOCNET 2014) & Demand Modeling and Quantitative Analysis of Future Generation Energy Networks and Energy-Efficient Systems (FGENET 2014)

At present, a comprehensive set of measurement, modeling, analysis, simulation, and performance evaluation techniques are employed to investigate complex networks. A direct transfer of the developed engineering methodologies to related analysis and design tasks in next-generation energy networks, energy-efficient systems and social networks is enabled by a common mathematical foundation. The International Workshop on "Demand Modeling and Quantitative Analysis of Future Generation Energy Networks and Energy-Efficient Systems" (FGENET 2014) and the International Workshop on "Modeling, Analysis and Management of Social Networks and their Applications" (SOCNET 2014) were held on March 19, 2014, at University of Bamberg in Germany as satellite symposia of the 17th International GI/ITG Conference on "Measurement, Modelling and Evaluation of Computing Systems" and "Dependability and Fault-Tolerance" (MMB & DFT 2014). They dealt with current research issues in next-generation energy networks, smart grid communication architectures, energy-efficient systems, social networks and social media. The Proceedings of MMB & DFT 2014 International Workshops summarizes the contributions of 3 invited talks and 13 reviewed papers and intends to stimulate the readers’ future research in these vital areas of modern information societies.Gegenwärtig wird eine reichhaltige Klasse von Verfahren zur Messung, Modellierung, Analyse, Simulation und Leistungsbewertung komplexer Netze eingesetzt. Die unmittelbare Übertragung entwickelter Ingenieurmethoden auf verwandte Analyse- und Entwurfsaufgaben in Energienetzen der nächsten Generation, energieeffizienten Systemen und sozialen Netzwerken wird durch eine gemeinsame mathematische Basis ermöglicht. Die Internationalen Workshops "Demand Modeling and Quantitative Analysis of Future Generation Energy Net-works and Energy-Efficient Systems" (FGENET 2014) und "Modeling, Analysis and Management of Social Networks and their Applications" (SOCNET 2014) wurden am 19. März 2014 als angegliederte Symposien der 17. Internationalen GI/ITG Konferenz "Measurement, Modelling and Evaluation of Computing Systems" und "Dependability and Fault-Tolerance" (MMB & DFT 2014) an der Otto-Friedrich-Universität Bamberg in Deutschland veranstaltet. Es wurden aktuelle Forschungsfragen in Energienetzen der nächsten Generation, Smart Grid Kommunikationsarchitekturen, energieeffizienten Systemen, sozialen Netzwerken und sozialen Medien diskutiert. Der Tagungsband der Internationalen Workshops MMB & DFT 2014 fasst die Inhalte von 3 eingeladenen Vorträgen und 13 begutachteten Beiträgen zusammen und beabsichtigt, den Lesern Anregungen für ihre eigenen Forschungen auf diesen lebenswichtigen Gebieten moderner Informationsgesellschaften zu vermitteln

<i>BRAF</i> V600E/<i>RAS</i> Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors

Abstract Background We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS). Patients and Methods Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAFV600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P &lt; .2) if limited number of events. Results Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 in the total population, 111 (24.0%) were treated in first-line; 129 (28.8%) were BRAFV600E-mutated and 153 (32.8%) RAS-mutated. Median follow-up was 20.9 months. In adjusted analysis of the whole population (PFS/OS events = 186/133), no associations with PFS and OS were observed for BRAFV600E-mutated (PFS HR= 1.20, P = .372; OS HR = 1.06, P = .811) and RAS-mutated patients (PFS HR = 0.93, P = .712, OS HR = 0.75, P = .202). In adjusted analysis in the Lynch/sporadic status-assigned population (n = 242; PFS/OS events = 80/54), LS-liked patients had an improved PFS compared to sporadic cases (HR = 0.49, P = .036). The adjusted HR for OS was 0.56 with no significance (P = .143). No adjustment on BRAFV600E mutation was done due to collinearity. Conclusion In this cohort, RAS/BRAFV600E mutations were not associated with survival while LS conferred an improved PFS

Adrenal gland as a sanctuary site for immunotherapy in patients with microsatellite instability-high metastatic colorectal cancer

International audienceMetastatic colorectal cancers (mCRC) harboring microsatellite instability (MSI) are sensitive to immune checkpoint inhibitors (ICIs), but the mechanisms of resistance to ICIs remain unclear. Dissociated responses in patients with ICI-treated cancer suggest that certain organs may serve as sanctuary sites due to the tumor microenvironment. This case series describes five patients with ICI-treated MSI mCRC with disease progression limited to the adrenal glands. At ICI initiation, three patients were free of metastasis in the adrenal glands. Four patients experienced objective response per RECIST (Response Evaluation Criteria in Solid Tumors) while treated with ICI. ICI treatment was discontinued due to progressive disease limited to the adrenal glands (n=3) or toxicity (n=2). The time between ICI initiation and progression in the adrenal glands ranged from 11 to 39 months. Adrenalectomy (n=3) and stereotactic body radiation therapy (n=2) were performed. At the last follow-up, all patients were alive and progression free. Molecular analyses were performed in one patient. A significant impairment of the antigen presentation pathway was observed in the ICI-resistant lesion of the adrenal gland, which could be explained by the presence of glucocorticoids in the adrenal gland microenvironment. We also detected an overexpression of TSC22D3, a glucocorticoid-target gene that functions as a mediator of anti-inflammation and immunosuppression. This case series suggests that the adrenal glands may be the sanctuary sites for ICI-treated MSI mCRC through the glucocorticoid-induced impairment of the antigen presentation machinery

Risk factors for Coronavirus Disease 2019 (COVID-19) severity and mortality among solid cancer patients and impact of the disease on anticancer treatment: A French nationwide cohort study (GCO-002 CACOVID-19).

International audienceBACKGROUND: Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. PATIENTS AND METHODS: In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and 11th June 2020. The primary end-point was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary end-points. RESULTS: From April 4 to 11th June 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), The Eastern Cooperative Oncology Group Performance Scale (ECOG PS) ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except for cytotoxic chemotherapy in the subgroup of patients with detectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcriptase polymerase chain reaction (RT-PCR), which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment (such as chemotherapy, targeted or immune therapy) interrupted or stopped following diagnosis of COVID-19. CONCLUSIONS: Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis