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Introduction: The use of osimertinib in the first-line (1L) setting is an effective treatment option for sensitizing EGFR-mutations (EGFRm+) and has significantly altered the standard of care practice for EGFRm+ disease in Canada. Unfortunately, acquired resistance to osimertinib is almost universal, and outcomes are disparate. Post-progression treatment patterns and the outcome of real-world Canadian EGFRm+ patients receiving 1L osimertinib were the focus of this retrospective review. Methods: The Glans-Look Lung Cancer Research database was used to identify and collect demographic, clinical, treatment, and outcome data on EGFRm+ patients who received 1L osimertinib in the Canadian province of Alberta between 2018 and 2022. Results: A total of 150 patients receiving 1L osimertinib were identified. In total, 86 developed progressive disease, with 56 (65%) continuing systemic therapy, 73% continuing osimertinib, and 27% switching to second-line (2L) systemic therapy. Patients were similar both in clinical characteristics at 1L osimertinib initiation and patterns of treatment failure at progression; those continuing 1L osimertinib post-progression had a longer time to progression (13.5 vs. 8.8 months, p = 0.05) and subsequent post-osimertinib initiation survival (34.7 vs. 22.8 months, p = 0.11). Conclusions: The continuation of osimertinib post-progression is an effective disease management strategy for select real-world EGFRm+ patients, providing continued clinical benefit, potentially due to different underlying disease pathogenesis. [ABSTRACT FROM AUTHOR]

The mechanisms by which cells undergo proliferation arrest or cell death in response to hypoxia are still not completely understood. Originally, we showed that HeLa and Hep3B carcinoma cells undergo different proliferation responses in hypoxia. We now show that these 2 cell lines also have different cell death responses to severe hypoxia, with HeLa showing both cell cycle arrest and apoptosis (as early as 12 h after hypoxia treatment), and Hep3B showing resistance to both. Hypoxia-induced apoptosis in Hela was associated with decreases of both phospho-S473- and -T308-AKT and loss of AKT function, whereas Hep3B cells were resistant to hypoxia-induced apoptosis and did not lose phosphoAKT or AKT function. We then decided to test if our observations were confirmed using a hypoxia mimic, desferoxamine. Desferoxamine treatment yielded cell cycle arrest in HeLa and moderate arrest in Hep3B but, surprisingly, did not induce notable apoptosis of either cell line with up to 24 h of treatment. Hypoxia-treated normal human mammary epithelial cells also showed hypoxia-induced apoptosis. Interestingly, in these cell lines, there was a complete correlation between loss of phospho-AKT and (or) total AKT, and susceptibility to hypoxia-induced apoptosis. Our data suggests a model in which regulated loss of active AKT at a precise time point in hypoxia may be associated with apoptosis in susceptible cells. Key words: AKT, apoptosis, cell cycle, desferoxamine, hypoxia. Les mecanismes par lesquels les cellules s'engagent vers l'arret de la proliferation ou la mort cellulaire en reponse a l'hypoxie ne sont pas encore completement compris. A l'origine, nous avons demontre que les cellules de carcinome HeLa et Hep3B repondent de facon differente a l'hypoxie en ce qui a trait a la proliferation. Nous demontrons maintenant que ces deux lignees cellulaires repondent aussi differemment quant a la mort cellulaire suite a une hypoxie severe, les HeLa repondant par un arret du cycle cellulaire et par l'apoptose (aussi toet que 12 h apres un traitement hypoxique) alors que les Hep3B etaient resistantes aux deux phenomenes. L'apoptose induite par l'hypoxie chez les HeLa etait associee a une diminution des formes phospho-S473- et -T308-AKT et a une perte de fonction de l'AKT, alors que chez les cellules Hep3B resistantes a l'apoptose induite par l'hypoxie, les formes phosphorylees de l'AKT n'etaient pas diminue es et la fonction de l'AKT n'etait pas perdue. Nous avons alors decide de verifier si nos observations se confirmaient avec un agent mimant l'apoptose, la desferoxamine. Le traitement a la desferoxamine causait un arret du cycle cellulaire des HeLa et un arret modere des Hep3B, mais, de facon surprenante, il n'induisait l'apoptose chez aucune de ces deux ligne es apres un traitement allant jusqu'a 24 h. Des cellules epitheliales mammaires humaines normales soumises a l'hypoxie entraient egalement en apoptose. Fait interessant, chez ces lignees cellulaires, il existait une correlation complete entre la perte des formes phosphorylees de l'AKT et (ou) de l'AKT totale et la susceptibilite a l'apoptose induite par l'hypoxie. Nos resultats suggerent l'existence d'un modele dans lequel une perte regulee d'AKT active a des moments precis de l'hypoxie peut etre associee a l'apoptose dans les cellules sensibles. Mots-cles : AKT, apoptose, cycle cellulaire, desferoxamine, hypoxie. [Traduit par la Redaction], Introduction Hypoxia plays a critical role in the development, progression, and treatment of a large number of cancers. In the initial stages of tumour formation, small tumours can quickly outstrip [...]

The Canadian NTRK (CANTRK) study is an interlaboratory comparison ring study to optimize testing for neurotrophic receptor tyrosine kinase (NTRK) fusions in Canadian laboratories. Sixteen diagnostic laboratories used next-generation sequencing (NGS) for NTRK1, NTRK2, or NTRK3 fusions. Each laboratory received 12 formalin-fixed, paraffin-embedded tumor samples with unique NTRK fusions and two control non-NTRK fusion samples (one ALK and one ROS1). Laboratories used validated protocols for NGS fusion detection. Panels included Oncomine Comprehensive Assay v3, Oncomine Focus Assay, Oncomine Precision Assay, AmpliSeq for Illumina Focus, TruSight RNA Pan-Cancer Panel, FusionPlex Lung, and QIAseq Multimodal Lung. One sample was withdrawn from analysis because of sample quality issues. Of the remaining 13 samples, 6 of 11 NTRK fusions and both control fusions were detected by all laboratories. Two fusions, WNK2::NTRK2 and STRN3::NTRK2, were not detected by 10 laboratories using the Oncomine Comprehensive or Focus panels, due to absence of WNK2 and STRN3 in panel designs. Two fusions, TPM3::NTRK1 and LMNA::NTRK1, were challenging to detect on the AmpliSeq for Illumina Focus panel because of bioinformatics issues. One ETV6::NTRK3 fusion at low levels was not detected by two laboratories using the TruSight Pan-Cancer Panel. Panels detecting all fusions included FusionPlex Lung, Oncomine Precision, and QIAseq Multimodal Lung. The CANTRK study showed competency in detection of NTRK fusions by NGS across different panels in 16 Canadian laboratories and identified key test issues as targets for improvements., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)