Systemic treatment of advanced biliary cancers: present and future

Deux essais randomisés de phase III récents ont démontré que les combinaisons gemcitabine – platine (schémas GEMOX et GEMCIS) étaient supérieures en termes de survie globale aux meilleurs soins de support et à la gemcitabine seule, respectivement, faisant de ces deux schémas les options thérapeutiques de choix en première ligne de traitement des patients atteints de cancers biliaires avancés. Si aucune donnée ne permet de définir actuellement de standard au-delà de la première ligne, un schéma à base de fluoropyrimidine peut être proposé sur la foi d’une revue systématique de plus de 100 essais de chimiothérapie. L’inhibition ciblée d’altérations moléculaires oncogéniques tumorales d’intérêt, comme l’activation de la voie EGFR ou de MEK, seule ou en association à la chimiothérapie, a permis d’obtenir des premiers résultats encourageants.Two randomized phase III trials have recently demonstrated that gemcitabine – platinum combinations (GEMOX and GEMCIS regimens) were superior in terms of overall survival over best supportive care and gemcitabine alone, respectively, making these two regimens treatment options of choice in first-line treatment of patients with advanced biliary cancers. Although no data are currently available beyond first-line therapy, fluoropyrimidinebased regimens can be proposed on the basis of a systematic review of over 100 trials of chemotherapy. The targeted inhibition of tumor oncogenic molecular alterations of interest such as EGFR pathway or MEK activation, alone or in combination with chemotherapy, has yielded encouraging results

Phase Ib/II Study of the Efficacy and Safety of Binimetinib (MEK162) Plus Panitumumab for Mutant or Wild-Type RAS Metastatic Colorectal Cancer

RAS mutation; Binimetinib; Colorectal cancerMutació RAS; Binimetinib; Càncer colorectalMutación RAS; Binimetinib; Cáncer colorrectalIntroduction Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to epidermal growth factor receptor (EGFR) blockade resistance. Combined EGFR and mitogen-activated protein kinase (MEK) inhibition may extend response to EGFR inhibition and overcome acquired resistance. This phase Ib/II dose escalation trial evaluated the safety and activity of dual inhibition with binimetinib (MEK1/2 inhibitor) and panitumumab (EGFR inhibitor [EGFRi]) in patients with RAS mutant or BRAF wild type (WT)/RAS WT mCRC. Methods Phase Ib dose escalation started with binimetinib 45 mg twice daily plus panitumumab 6 mg/kg administered every 2 weeks. In the phase II study, patients with measurable mCRC were enrolled into 4 groups based on previous anti-EGFR monoclonal antibody therapy and RAS mutational status. Results No patients in the phase Ib portion (n = 10) had a response; 70% of patients had stable disease. In the phase II portion (n = 43), overall response rate (ORR, confirmed) was 2.3% with one partial response in the RAS WT group, DCR was 30.2%, and median progression-free survival was 1.8 months (95%CI, 1.6-3.3). All patients experienced ≥1 adverse event, with the most common being diarrhea (71.7%), vomiting (52.8%), nausea (50.9%), fatigue (49.1%), dermatitis acneiform (43.4%), and rash (41.5%). Most patients required treatment interruption or dose reduction due to difficulties tolerating treatment. Conclusions The combination of binimetinib and panitumumab had substantial toxicity and limited clinical activity for patients with mutant or WT RAS mCRC, independent of EGFRi treatment history (Trial registration: NCT01927341).This study was sponsored by Array Biopharma in collaboration with Novartis. Array Biopharma was acquired by Pfizer in July 2019. Medical writing and editorial assistance were provided by Namiko Abe of Caudex and were funded by Pfizer. Research was supported by the National Institutes of Health Cancer Center Core Grant P30 CA 008748

Review of the current status of RAS mutation testing in patients with metastatic colorectal cancer (mCRC): Flash-RAS study

Présentation PosterInternational audienceOBJECTIVES: In 2013, it was shown that mutations in KRAS exons 3 and 4, or NRAS exons 2 to 4 had a similar effect. The primary objective was to assess the practices in conducting RAS testing in 2014. The secondary objectives were to describe the evolution of the RAS testing prescription rates from 2011, the process and time required to obtain the results, and to analyze their impact on the therapeutic strategy. METHODS: FLASH-RAS is an observational retrospective French multicenter study. RESULTS: 375 mCRC patients diagnosed and initiating a 1st line treatment (L1) between March and June 2014 were analyzed. For 90.1% of the patients (IC95%= [87.1%; 93.2%]), a genotyping request for RAS biomarkers was made in L1, i.e. a significantly increased rate compared to 2011 (81.1% in 2011, p<0.001). For 75% of the patients, the request was made before or at least one month after the diagnosis of the first metastases (1st M). No increase was observed in the median and mean times to obtain the test results between 2011 and 2014 despite the increased number of exons tested. CONCLUSIONS: In 2014, the rate of RAS genotyping requests has been increasing since 2011. For a majority of patients, the request is made before or at the latest one month after 1st M diagnosis. Nevertheless, for 24.5% of the patients, the request is made more than one month after 1st M diagnosis, which is not compatible with an informed treatment decision in L1

Global ph 3, randomized, double-blind, placebo-controlled study of PEGylated recombinant human hyaluronidase PH20 (PEGPH20) + nab-paclitaxel & gemcitabine in pts with previously untreated, hyaluronan-high, stage iv pancreatic ductal adenocarcinoma

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Disseminated and circulating tumor cells in gastrointestinal oncology.

International audienceCirculating (CTCs) and disseminated tumor cells (DTCs) are two different steps in the metastatic process. Several recent techniques have allowed detection of these cells in patients, and have generated many results using different isolation techniques in small cohorts. Herein, we review the detection results and their clinical consequence in esophageal, gastric, pancreatic, colorectal, and liver carcinomas, and discuss their possible applications as new biomarkers

Junctate is a key element in calcium entry induced by activation of InsP3 receptors and/or calcium store depletion

In many cell types agonist-receptor activation leads to a rapid and transient release of Ca2+ from intracellular stores via activation of inositol 1,4,5 trisphosphate (InsP3) receptors (InsP3Rs). Stimulated cells activate store- or receptor-operated calcium channels localized in the plasma membrane, allowing entry of extracellular calcium into the cytoplasm, and thus replenishment of intracellular calcium stores. Calcium entry must be finely regulated in order to prevent an excessive intracellular calcium increase. Junctate, an integral calcium binding protein of endo(sarco)plasmic reticulum membrane, (a) induces and/or stabilizes peripheral couplings between the ER and the plasma membrane, and (b) forms a supramolecular complex with the InsP3R and the canonical transient receptor potential protein (TRPC) 3 calcium entry channel. The full-length protein modulates both agonist-induced and store depletion–induced calcium entry, whereas its NH2 terminus affects receptor-activated calcium entry. RNA interference to deplete cells of endogenous junctate, knocked down both agonist-activated calcium release from intracellular stores and calcium entry via TRPC3. These results demonstrate that junctate is a new protein involved in calcium homeostasis in eukaryotic cells

Efficacy, safety, and pharmacokinetics of the anti-programmed cell death receptor-1 (PD-1) monoclonal antibody, tislelizumab (BGB-A317) in a phase 2, open-label, multicenter study to investigate in patients with unresectable hepatocellular carcinoma - Trial in progress.

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