Real-world treatment patterns and clinical outcomes for chemotherapy-based regimens in first-line MSI-H/dMMR metastatic colorectal cancer.

MICRO ABSTRACT: This retrospective observational study assessed real-world treatment patterns and clinical outcomes among first-line MSI-H/dMMR metastatic colorectal cancer patients. Of 150 patients in the study cohort, 38.7% were treated with chemotherapy and 61.3% with chemotherapy + EGFR/VEGF inhibitor (EGFRi/VEGFi). Clinical outcomes were better among patients who received chemotherapy + EGFR/VEGF inhibitor than those who received chemotherapy. INTRODUCTION: Prior to pembrolizumab approval in first-line (1L) treatment of MSI-H/dMMR metastatic colorectal cancer (mCRC), patients were managed with chemotherapy with or without an EGFRi or VEGFi, agnostic of biomarker testing or mutation status. This study assessed real-world treatment patterns and clinical outcomes among 1L MSI-H/dMMR mCRC patients treated with standard of care (SOC). PATIENTS AND METHODS: Retrospective observational evaluation of patients ≥18 years diagnosed with stage IV MSI-H/dMMR mCRC who received community-based oncology care. Eligible patients were identified (01-Jun-2017 - 29-Feb-2020) and followed longitudinally until 31-Aug-2020/the last patient record/date of death. Descriptive statistics and Kaplan-Meier analyses were conducted. RESULTS: Of 150 1L MSI-H/dMMR mCRC patients, 38.7% were treated with chemotherapy and 61.3% with chemotherapy + EGFRi/VEGFi. Accounting for censoring, the overall median real-world time to treatment discontinuation (95% CI) was 5.3 (4.4, 5.8) months; 3.0 (2.1, 4.4) and 6.2 (5.5, 7.6) months in the chemotherapy and chemotherapy + EGFRi/VEGFi cohorts, respectively. The combined median overall survival was 27.7 (23.2, not reached [NR]) months; 25.3 (14.5, NR) and 29.8 (23.2, NR) months in the chemotherapy and chemotherapy + EGFRi/VEGFi cohorts, respectively. The overall median real-world progression-free survival was 6.8 (5.3, 7.8) months; 4.2 (2.8, 6.1) and 7.7 (6.1, 10.2) months in the chemotherapy and chemotherapy + EGFRi/VEGFi cohorts, respectively. CONCLUSIONS: 1L MSI-H/dMMR mCRC patients receiving chemotherapy with EGFRi/VEGFi had better outcomes than those receiving only chemotherapy. An unmet need and opportunity to improve outcomes exists in this population that may be addressed by newer treatments like immunotherapies.

Evolution of predictive and prognostic biomarkers in the treatment of advanced gastric cancer.

Despite new therapeutic options, advanced gastric cancer remains associated with a poor prognosis compared with other cancers. Recent gains in the treatment of gastric cancer were accompanied by the identification of novel biomarkers associated with various cellular pathways and corresponding diagnostic technologies. It is expected that the standardization of clinical workflow and technological refinements in biomarker assessment will support greater personalization and further improve treatment outcomes. In this article, we review the current state of prognostic and predictive biomarkers in gastric cancer.

CLASP1 regulates endothelial cell branching morphology and directed migration.

Endothelial cell (EC) branching is critically dependent upon the dynamic nature of the microtubule (MT) cytoskeleton. Extracellular matrix (ECM) mechanosensing is a prominent mechanism by which cytoskeletal reorganization is achieved; yet how ECM-induced signaling is able to target cytoskeletal reorganization intracellularly to facilitate productive EC branching morphogenesis is not known. Here, we tested the hypothesis that the composition and density of the ECM drive the regulation of MT growth dynamics in ECs by targeting the MT stabilizing protein, cytoplasmic linker associated protein 1 (CLASP1). High-resolution fluorescent microscopy coupled with computational image analysis reveal that CLASP1 promotes slow MT growth on glass ECMs and promotes short-lived MT growth on high-density collagen-I and fibronectin ECMs. Within EC branches, engagement of either high-density collagen-I or high-density fibronectin ECMs results in reduced MT growth speeds, while CLASP1-dependent effects on MT dynamics promotes elevated numbers of short, branched protrusions that guide persistent and directed EC migration.

MCAK-mediated regulation of endothelial cell microtubule dynamics is mechanosensitive to myosin-II contractility.

Compliance and dimensionality mechanosensing, the processes by which cells sense the physical attributes of the extracellular matrix (ECM), are known to drive cell branching and shape change largely through a myosin-II-mediated reorganization of the actin and microtubule (MT) cytoskeletons. Subcellular regulation of MT dynamics is spatially controlled through a Rac1-Aurora-A kinase pathway that locally inhibits the MT depolymerizing activity of mitotic centromere-associated kinesin (MCAK), thereby promoting leading-edge MT growth and cell polarization. These results suggest that the regulation of MT growth dynamics is intimately linked to physical engagement of the cell with the ECM. Here, we tested the hypothesis that MCAK contributes to compliance and dimensionality mechanosensing-mediated regulation of MT growth dynamics through a myosin-II-dependent signaling pathway. We cultured endothelial cells (ECs) on collagen-coupled stiff or compliant polyacrylamide ECMs to examine the effects of MCAK expression on MT growth dynamics and EC branching morphology. Our results identify that MCAK promotes fast MT growth speeds in ECs cultured on compliant 2D ECMs but promotes slow MT growth speeds in ECs cultured on compliant 3D ECMs, and these effects are myosin-II dependent. Furthermore, we find that 3D ECM engagement uncouples MCAK-mediated regulation of MT growth persistence from myosin-II-mediated regulation of growth persistence specifically within EC branched protrusions.