Current treatment options in RAS mutant metastatic colorectal cancer patients: a meta-analysis of 14 randomized phase III trials
RAS 突变转移性结直肠癌患者的当前治疗选择: 14 项随机 III 期试验的荟萃分析
- 作者列表："Stahler, Arndt","Heinemann, Volker","Ricard, Ingrid","Einem, Jobst C.","Giessen-Jung, Clemens","Westphalen, Christoph Benedikt","Michl, Marlies","Heinrich, Kathrin","Miller-Phillips, Lisa","Jelas, Ivan","Stintzing, Sebastian","Modest, Dominik Paul
Purpose Although biomarkers for patients with metastatic colorectal cancer exist, the benefit patients with RAS mutated tumors derive from established regimens is unclear. Methods Efficacy of therapeutic strategies available for RAS mutated patients (addition of chemotherapeutic agents and/or anti angiogenic agents) were investigated in fourteen randomized controlled phase III trials at trial level by meta-analysing individual study hazard ratios and 95% confidence intervals (95% CI) for overall survival (OS) and progression free survival (PFS). Results 6810 of 10,748 patients (63.3%) were available (48.5% RAS wildtype, 51.5% RAS mutated). Across all treatment lines, additional treatment efficacy (chemotherapy and/or anti angiogenic agents) was significantly smaller in RAS mutated compared to wildtype tumors for OS and PFS. In detail, patients with RAS mutated metastatic colorectal cancer derived significant benefit in PFS but not in OS by the addition of either chemotherapy or anti angiogenic agents to the respective comparator. In patients with RAS wildtype metastatic colorectal cancer, PFS and OS were improved by the addition of chemotherapy or anti angiogenic agent. Conclusion The therapeutic benefit of additional substances is less distinct in patients with RAS mutated as compared to RAS wildtype metastatic colorectal cancer, especially with regard to OS.
目的虽然存在转移性结直肠癌患者的生物标志物，但 RAS 突变肿瘤患者从已建立的方案中获得的益处尚不清楚。方法: RAS 突变患者可用治疗策略的疗效 (添加化疗药物和/或抗血管生成药物) 通过荟萃分析个体研究风险比和总生存期 (OS) 的 95% 置信区间 (95% CI)，在试验水平对 14 个随机对照 III 期试验进行了调查和无进展生存期 (PFS)。结果 6810 例患者中有 10,748 例 (63.3%) 可用 (48.5% RAS 野生型，51.5% RAS 突变)。在所有治疗线上，与 OS 和 PFS 的野生型肿瘤相比，RAS 突变的附加治疗疗效 (化疗和/或抗血管生成剂) 显著较小。详细来说，RAS 突变的转移性结直肠癌患者通过在各自的对照物中加入化疗或抗血管生成药物，在 PFS 中获得显著获益，但在 OS 中没有显著获益。在 RAS 野生型转移性结直肠癌患者中，加用化疗或抗血管生成剂可改善 PFS 和 OS。结论与 RAS 野生型转移性结直肠癌相比，在 RAS 突变的患者中，额外物质的治疗益处不太明显，尤其是在 OS 方面。
METHODS::Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (Engulfment and Cell Motility Protein-1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem-cell-based "gut-in-a-dish" coculture model, we studied the interactions between microbes, epithelium and monocytes in the context of IBD. To mimic the in-vivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.
METHODS:BACKGROUND:Peripheral blood eosinophilia (PBE) is a biomarker of an aggressive multiyear natural history in adults with inflammatory bowel diseases (IBDs). Additionally, PBE at diagnosis is associated with higher disease activity in pediatric-onset IBD. We sought to determine if PBE can function as a biomarker of long-term disease severity in pediatric-onset IBD patients who are followed into adulthood. METHODS:We analyzed a consented, prospective, natural history IBD registry at an adult tertiary center from 2009 to 2018. Prevalence of PBE was evaluated in both pediatric- and adult-onset IBD patients. Demographics, clinical characteristics, and health care utilization data were compared in patients with and without PBE. RESULTS:Among 2800 adult IBD patients, 23.4% had pediatric-onset disease. PBE was found in 34% of the pediatric-onset patients compared with 26.8% of the adult-onset IBD patients (P < 0.001). In the pediatric-onset IBD cohort, PBE was associated with higher rates of allergies (P < 0.0001), but not of asthma, allergic rhinitis, or primary sclerosing cholangitis. In the adult IBD patients with pediatric-onset disease, PBE was associated with higher rates of C-reactive protein elevation (P < 0.0001), erythrocyte sedimentation rate elevation (P < 0.0001), higher health care utilization, and higher average health care charges per year (P < 0.00001). CONCLUSIONS:Peripheral blood eosinophilia was more prevalent in adult IBD patients with pediatric-onset compared with adult-onset disease. Among all IBD patients with long-term follow-up, PBE defined a subgroup with more severe illness. These data suggest that PBE may be a biomarker for a high-risk subgroup with high cost trajectory and long-term severity in pediatric-onset IBD that persists into adulthood.
METHODS::Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.